Is TXNRD2 p.Pro517Ser (c.1549C>T) pathogenic?

TXNRD2 p.Pro517Ser (c.1549C>T) is classified Uncertain significance in TXNRD2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-23). Ultra-rare (popmax 0.0254%, afr); Associated with Cardiovascular phenotype.

What condition is associated with TXNRD2 p.Pro517Ser (c.1549C>T)?

TXNRD2 p.Pro517Ser (c.1549C>T) is associated with Cardiovascular phenotype, dilated cardiomyopathy (ClinVar).

How common is TXNRD2 p.Pro517Ser (c.1549C>T) in the general population?

TXNRD2 p.Pro517Ser (c.1549C>T) is ultra-rare (popmax 0.0254%, afr) (gnomAD).

TXNRD2 p.Pro517Ser

c.1549C>T · rs756196216 · VCV1470688

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.148	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.5, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 46 bp · p 0.0019 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0254% African / African-American · 19/74,664 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.00137% 22/1,601,126 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0254%	3,930
East Asian	0.0045%	22,246
Remaining individualsnot grpmax-eligible	0.00162%	61,764

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.Pro517Ser
Coding: c.1549C>T
MANE Select: NM_006440
dbSNP: rs756196216
Type: single nucleotide variant
Location: chr22:19877131 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Residue 517: 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.Pro517Thr Uncertain significance ★★ same residue
TXNRD2 p.Pro517His 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-pro517ser (accessed [today's date]).

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