Is TXNRD2 p.Arg286Ser (c.858G>C) pathogenic?

TXNRD2 p.Arg286Ser (c.858G>C) is classified Conflicting classifications of pathogenicity in TXNRD2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-15). Rare (popmax 0.126%, nfe); Associated with TXNRD2-related disorder.

What condition is associated with TXNRD2 p.Arg286Ser (c.858G>C)?

TXNRD2 p.Arg286Ser (c.858G>C) is associated with TXNRD2-related disorder, dilated cardiomyopathy (ClinVar).

How common is TXNRD2 p.Arg286Ser (c.858G>C) in the general population?

TXNRD2 p.Arg286Ser (c.858G>C) is rare (popmax 0.126%, nfe) (gnomAD).

TXNRD2 p.Arg286Ser

c.858G>C · rs201503021 · VCV414282

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.126%, nfe)

Conditions

TXNRD2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.058	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.045	GERP -1.2, phastCons 0.001
Regional constraint	o/e 0.88	unconstrained · MANE · 65 kb · p 0.0019 · regional, not allelic
Overall
CADD	14.03	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.126% European (non-Finnish) · 1,483/1,180,040 alleles

Filtering AF 0.12% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.118%

Overall 0.104% 1,671/1,613,794 alleles · rare exomes 1,557/1,461,578 · genomes 114/152,216 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.987%	101
European (non-Finnish)grpmax	0.126%	796
Remaining individualsnot grpmax-eligible	0.11%	906
South Asian	0.0747%	1,340
Admixed American	0.025%	4,001
African / African-American	0.0227%	4,408
Finnishnot grpmax-eligible	0.0141%	7,082
East Asian	0.00223%	44,896

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg286Ser
Coding: c.858G>C
MANE Select: NM_006440
dbSNP: rs201503021
Type: single nucleotide variant
Location: chr22:19895498 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)

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

Disease context

TXNRD2-related disorder

Also linked: dilated cardiomyopathy

Similar variants

TXNRD2 p.Arg286= Likely benign ★★ 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
TXNRD2 c.1445+5G>C 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-arg286ser (accessed [today's date]).

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