Is TXNRD2 p.Ser299Arg (c.895A>C) pathogenic?

TXNRD2 p.Ser299Arg (c.895A>C) is classified Benign in TXNRD2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 52.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with dilated cardiomyopathy.

What condition is associated with TXNRD2 p.Ser299Arg (c.895A>C)?

TXNRD2 p.Ser299Arg (c.895A>C) is associated with dilated cardiomyopathy (ClinVar).

TXNRD2 p.Ser299Arg

Q: How common is TXNRD2 p.Ser299Arg (c.895A>C) in the general population?

TXNRD2 p.Ser299Arg (c.895A>C) is common (popmax 52.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.895A>C · rs5992495 · VCV263411

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 52.3%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

dilated cardiomyopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.015	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.23	GERP -2.5
Regional constraint	o/e 0.88	unconstrained · MANE · 65 kb · p 0.0019 · regional, not allelic
Overall
CADD	0.008	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 52.3% African / African-American · 39,227/74,978 alleles

Filtering AF 51.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 51.7%

Overall 18.3% 294,871/1,613,808 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	52.3%	2
South Asian	20.1%	5
Middle Eastern	19.3%	5
Ashkenazi Jewishnot grpmax-eligible	19.1%	5
Remaining individualsnot grpmax-eligible	18.5%	5
European (non-Finnish)	16.9%	6
Admixed American	15.8%	6
Finnishnot grpmax-eligible	12.9%	8
Amishnot grpmax-eligible	7.46%	13
East Asian	5.22%	19

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.Ser299Arg
Coding: c.895A>C
MANE Select: NM_006440
dbSNP: rs5992495
Type: single nucleotide variant
Location: chr22:19895461 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Residue 299: a UniProt-annotated variant site (in)

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

Disease context

dilated cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TXNRD2 p.Ser299Cys Uncertain significance ★★ same residue
TXNRD2 p.Ser299Asn 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.1348-2A>G Uncertain significance ★★ same condition
TXNRD2 c.1348-9G>A 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-ser299arg (accessed [today's date]).

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