rs76992529

badMag 8.5

This is a variant in the TTR gene that changes a valine to an isoleucine.

Key Literature Trait Associations

Hereditary Transthyretin Amyloidosis

The Val122Ile variant (rs76992529-A) in TTR is a well-established pathogenic cause of hereditary transthyretin amyloidosis (ATTRv), classified as Pathogenic by ClinVar with multiple submitter consensus. It is carried by approximately 3.4% of African Americans (~1.5 million US individuals) and originates from a West African founder population. Clinically, ATTRv Val122Ile manifests primarily as cardiomyopathy, typically presenting in Black men after age 60, though peripheral neuropathy and carpal tunnel syndrome can also occur. Penetrance is incomplete but substantially elevated; heterozygous carriers face meaningful lifetime risk, and a rare homozygous presentation has been documented with severe early-onset cardiac disease. FDA-approved tafamidis reduces mortality and hospitalizations w...

Ruberg FL et al. “Cardiac Amyloidosis Due to Transthyretin Protein: A Review.” Jama (2024)

Allele A

OR —

p —

Candidate gene study

multi-ancestry

De Lillo A et al. “Clinical spectrum of Transthyretin amyloidogenic mutations among diverse population origins.” Human Genomics (2024)

Allele A

OR —

p 2.0e-3

N 13,106

Preliminary work

multi-ancestry

Neculae G et al. “A phenotypic comparison of the Romanian and French ATTRv cohorts: Glu54Gln founder pathogenic variant vs the most common variants in Western Europe.” International Journal of Cardiology (2025)

Allele A

OR —

p —

N 291

Candidate gene study

multi-ancestry

Shije JZ et al. “The Frequency of V122I Transthyretin Mutation in a Cohort of African American Individuals With Bilateral Carpal Tunnel Syndrome.” Frontiers in Neurology (2022)

Allele A

OR —

p —

N 16

Candidate gene study

African American

Ruberg FL et al. “Design and Rationale the SCAN-MP (Screening for Cardiac Amyloidosis With Nuclear Imaging in Minority Populations) Study.” Journal of the American Heart Association (2023)

Allele A

OR —

p —

Candidate gene study

African American

Barker N et al. “Counseling Family Members and Monitoring for Evidence of Disease in Asymptomatic Carriers of Amyloid Transthyretin Cardiac Amyloidosis.” The American Journal of Cardiology (2022)

Allele A

OR —

p —

Candidate gene study

African American

Obi CA et al. “ATTR Epidemiology, Genetics, and Prognostic Factors.” Methodist Debakey Cardiovascular Journal (2022)

Allele A

OR —

p —

Candidate gene study

multi-ancestry

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GWAS Catalog Trait Associations (1)

Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.

metabolite measurement

Tahir UA et al. “Whole Genome Association Study of the Plasma Metabolome Identifies Metabolites Linked to Cardiometabolic Disease in Black Individuals.” Nature Communications 13(1):4923 (2022)

Allele A

OR 0.76

p 5.0e-14

N 2,466

Large GWAS

multi-ancestry

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ClinVar annotation

Pathogenic★★★☆

51 submitters111 publications

ATTRV122I amyloidosis; Amyloidosis; Amyloidosis, hereditary systemic 1 (AMYLD1); Cardiomyopathy (CMYO); Cardiovascular phenotype; Carpal tunnel syndrome 1 (CTS1); Charcot-Marie-Tooth disease; Hyperthyroxinemia, dystransthyretinemic; TTR-related disorder; Tip-toe gait

View on ClinVar →

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Research that mentions this SNP (1)

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OtherN=450Unknown

This is a journal issue containing multiple brief communications published in Annals of Neurology (2000;47:511-531). Key studies include: (1) Two sisters with reversible brain creatine deficiency responsive to creatine supplementation despite normal blood creatine levels; (2) A novel sonic hedgehog (SHH) gene signal peptide mutation (T-to-C at position 50, predicting leucine-to-proline change at codon 17) in a patient with lobar holoprosencephaly; (3) A three-generation dopa-responsive dystonia family with a large GCH1 gene deletion undetectable by standard sequencing; (4) A dopamine transporter (DAT) polymorphism study showing 1215A/G (exon 9) and 1898T/C (exon 15) variants, with 1215G protective against Parkinson's disease (OR=2.07 for non-carriers); (5) Nitrotyrosine-containing protein (Mn-SOD) elevated in Parkinson's, Alzheimer's and ALS cerebrospinal fluid; (6) Cardiac amyloidosis with TTR gene Val122Ile mutation associated with sporadic IBM.

Traits studied:Alzheimer's diseaseAmyotrophic lateral sclerosisBrain creatine deficiencyCardiac amyloidosisDopa-responsive dystoniaHoloprosencephalyMyopathy with apoptosisParkinson's diseaseProgressive supranuclear palsySporadic inclusion body myositis

rs76992529

Key Literature Trait Associations

Hereditary Transthyretin Amyloidosis

GWAS Catalog Trait Associations (1)

metabolite measurement

ClinVar annotation

Research that mentions this SNP (1)

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