Is TXN2 p.Ala12Val (c.35C>T) pathogenic?

TXN2 p.Ala12Val (c.35C>T) is classified Uncertain significance in TXN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-03-30). AlphaMissense: likely benign (0.1022); Ultra-rare (popmax 0.0643%, sas).

How common is TXN2 p.Ala12Val (c.35C>T) in the general population?

TXN2 p.Ala12Val (c.35C>T) is ultra-rare (popmax 0.0643%, sas) (gnomAD).

What do computational predictors say about TXN2 p.Ala12Val (c.35C>T)?

AlphaMissense predicts likely benign (score 0.1022) — an in-silico prediction, not a clinical call.

TXN2 p.Ala12Val

c.35C>T · rs534944987 · VCV446043

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1022 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0643%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1022	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -6.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.23	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 2.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 13 kb · p 0.016 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0643% South Asian · 58/90,238 alleles

Filtering AF 0.051% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0462%

Overall 0.00399% 64/1,603,470 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0643%	1,556
Middle Eastern	0.0335%	2,986
European (non-Finnish)	0.000341%	293,486

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: TXN2
Protein: p.Ala12Val
Coding: c.35C>T
MANE Select: NM_012473
dbSNP: rs534944987
Type: single nucleotide variant
Location: chr22:36480803 (GRCh38)
Gene constraint: LOEUF 1.358 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.10 · 3 PDB

Full TXN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TXN2 p.Ala12= Likely benign ★ same residue
TXN2 p.Ile126Val Uncertain significance ★★ ⚠ same type
TXN2 p.Ile165Thr Uncertain significance ★★ ⚠ same type
TXN2 p.Pro98Leu Uncertain significance ★★ ⚠ same type
TXN2 p.Ser29Cys Uncertain significance ★★ ⚠ same type
TXN2 c.387+30A>C Benign ★★ same type
TXN2 c.388-99C>A Benign ★★ same type
TXN2 p.Ala87= Likely benign ★★ 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/txn2-p-ala12val (accessed [today's date]).

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