Is TXNRD2 p.Ala488Val (c.1463C>T) pathogenic?

TXNRD2 p.Ala488Val (c.1463C>T) is classified Conflicting classifications of pathogenicity in TXNRD2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-10). Very rare (popmax 0.00439%, sas); Associated with Cardiovascular phenotype.

What condition is associated with TXNRD2 p.Ala488Val (c.1463C>T)?

TXNRD2 p.Ala488Val (c.1463C>T) is associated with Cardiovascular phenotype, dilated cardiomyopathy (ClinVar).

How common is TXNRD2 p.Ala488Val (c.1463C>T) in the general population?

TXNRD2 p.Ala488Val (c.1463C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

TXNRD2 p.Ala488Val

c.1463C>T · rs752947034 · VCV1055823

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.16	moderately benign-leaning
Splicing
SpliceAI	Δ0.24	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 0.32	GERP -2.3
Regional constraint	o/e 0.88	unconstrained · MANE · 65 kb · p 0.0019 · regional, not allelic
Overall
CADD	8.085	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,054 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000745% 12/1,610,916 alleles · very rare exomes 9/1,458,840 · genomes 3/152,076 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,763
Admixed American	0.00334%	29,978
Remaining individualsnot grpmax-eligible	0.00321%	31,179
African / African-American	0.00134%	74,858
European (non-Finnish)	0.000255%	392,793

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TXNRD2
Protein: p.Ala488Val
Coding: c.1463C>T
MANE Select: NM_006440
dbSNP: rs752947034
Type: single nucleotide variant
Location: chr22:19877217 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Residue 488: a UniProt-annotated variant site (in gccd5; the mutant protein is undetectable in patient cells)

Full TXNRD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy

Similar variants

TXNRD2 p.Ala488= Likely benign ★★ same residue
TXNRD2 p.Ala488Ser Uncertain significance ★ same residue
TXNRD2 c.104-1G>A Uncertain significance ★★ same condition
TXNRD2 c.104-3C>G Uncertain significance ★★ same condition
TXNRD2 c.1086+4C>T Uncertain significance ★★ same condition
TXNRD2 c.1087-2A>G Uncertain significance ★★ same condition
TXNRD2 c.1182+5G>A Uncertain significance ★★ same condition
TXNRD2 c.1348-2A>G Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/txnrd2-p-ala488val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown