Is TXNRD2 p.Ala66= (c.198C>T) pathogenic?

TXNRD2 p.Ala66= (c.198C>T) is classified Likely benign in TXNRD2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-16). Very rare (popmax 0.00545%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with TXNRD2 p.Ala66= (c.198C>T)?

TXNRD2 p.Ala66= (c.198C>T) is associated with Cardiovascular phenotype, dilated cardiomyopathy (ClinVar).

How common is TXNRD2 p.Ala66= (c.198C>T) in the general population?

TXNRD2 p.Ala66= (c.198C>T) is very rare (popmax 0.00545%, nfe) (gnomAD).

TXNRD2 p.Ala66=

c.198C>T · rs1009388190 · VCV1783935

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00545%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.6	GERP -3.1
Overall
CADD	6.252	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00545% European (non-Finnish) · 63/1,155,286 alleles

Filtering AF 0.00436% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00396%

Overall 0.00428% 67/1,564,122 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00545%	18,338
Remaining individualsnot grpmax-eligible	0.00494%	20,227
Admixed American	0.00191%	52,310

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.Ala66=
Coding: c.198C>T
MANE Select: NM_006440
dbSNP: rs1009388190
Type: single nucleotide variant
Location: chr22:19919574 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Residue 66: a UniProt-annotated variant site (in); a binding site

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.Ala66Ser 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.1182+5G>A 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-ala66 (accessed [today's date]).

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