Is TXNRD2 p.Ala488Ser (c.1462G>T) pathogenic?

TXNRD2 p.Ala488Ser (c.1462G>T) is classified Uncertain significance in TXNRD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-13). Very rare (popmax 0.00333%, amr).

How common is TXNRD2 p.Ala488Ser (c.1462G>T) in the general population?

TXNRD2 p.Ala488Ser (c.1462G>T) is very rare (popmax 0.00333%, amr) (gnomAD).

TXNRD2 p.Ala488Ser

c.1462G>T · rs757179801 · VCV2430625

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.101	moderately benign-leaning
Splicing
SpliceAI	Δ0.60	acceptor gain · deltas
Pangolin	Δ0.30	gain · loss 0.08 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.018	GERP 0.36
Regional constraint	o/e 0.88	unconstrained · MANE · 65 kb · p 0.0019 · regional, not allelic
Overall
CADD	14.08	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,972 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000248% 4/1,611,064 alleles · very rare exomes 4/1,458,876 · genomes 0/152,188 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,986
South Asian	0.0022%	45,526

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.Ala488Ser
Coding: c.1462G>T
MANE Select: NM_006440
dbSNP: rs757179801
Type: single nucleotide variant
Location: chr22:19877218 (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

Similar variants

TXNRD2 p.Ala488= Likely benign ★★ same residue
TXNRD2 p.Ala488Val Conflicting classifications of pathogenicity ★ same residue
TXNRD2 c.104-1G>A Uncertain significance ★★ same type
TXNRD2 c.104-3C>G Uncertain significance ★★ same type
TXNRD2 c.1086+4C>T Uncertain significance ★★ same type
TXNRD2 c.1087-2A>G Uncertain significance ★★ same type
TXNRD2 c.1182+5G>A Uncertain significance ★★ same type
TXNRD2 c.1348-2A>G Uncertain significance ★★ same type

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-ala488ser (accessed [today's date]).

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