Is TMX2 p.Arg111Pro (c.332G>C) pathogenic?

TMX2 p.Arg111Pro (c.332G>C) is classified Uncertain significance in TMX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-12). AlphaMissense: likely pathogenic (0.713); Ultra-rare (popmax 0.0111%, eas); Associated with Inborn genetic diseases.

What condition is associated with TMX2 p.Arg111Pro (c.332G>C)?

TMX2 p.Arg111Pro (c.332G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TMX2 p.Arg111Pro (c.332G>C) in the general population?

TMX2 p.Arg111Pro (c.332G>C) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about TMX2 p.Arg111Pro (c.332G>C)?

AlphaMissense predicts likely pathogenic (score 0.713) — an in-silico prediction, not a clinical call.

TMX2 p.Arg111Pro

c.332G>C · rs553831131 · VCV3180098

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.713 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.713	likely pathogenic
REVEL	0.599	indeterminate
SaProt	LLR -11.09	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,275 bp · p 0.036 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0111% East Asian · 5/44,872 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000372% 6/1,613,466 alleles · ultra-rare exomes 5/1,461,676 · genomes 1/151,790 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,974
European (non-Finnish)	8.48e-05%	1,179,876

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: TMX2
Protein: p.Arg111Pro
Coding: c.332G>C
MANE Select: NM_015959
dbSNP: rs553831131
Type: single nucleotide variant
Location: chr11:57737994 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.38 · 2 PDB

Full TMX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMX2 p.Ala2Val Uncertain significance ★★ ⚠ same condition
TMX2 p.Met112Val Uncertain significance ★★ ⚠ same condition
TMX2 p.Gly48Arg Likely benign ★★ same condition
TMX2 p.Ala229Thr Uncertain significance ★ ⚠ same condition
TMX2 p.Ala22Val Uncertain significance ★ ⚠ same condition
TMX2 p.Ala5Thr Uncertain significance ★ ⚠ same condition
TMX2 p.Ala9Ser Uncertain significance ★ ⚠ same condition
TMX2 p.Arg107Cys 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/tmx2-p-arg111pro (accessed [today's date]).

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