Is TMX2 p.Ala2Val (c.5C>T) pathogenic?

TMX2 p.Ala2Val (c.5C>T) is classified Uncertain significance in TMX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-05-08). AlphaMissense: ambiguous (0.5533); Ultra-rare (popmax 0.0251%, amr); Associated with Inborn genetic diseases.

What condition is associated with TMX2 p.Ala2Val (c.5C>T)?

TMX2 p.Ala2Val (c.5C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TMX2 p.Ala2Val (c.5C>T) in the general population?

TMX2 p.Ala2Val (c.5C>T) is ultra-rare (popmax 0.0251%, amr) (gnomAD).

What do computational predictors say about TMX2 p.Ala2Val (c.5C>T)?

AlphaMissense predicts ambiguous (score 0.5533) — an in-silico prediction, not a clinical call.

TMX2 p.Ala2Val

c.5C>T · VCV4865772

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5533 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0251%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5533	ambiguous
REVEL	0.177	moderately benign-leaning
SaProt	LLR -6.09	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.28	unconstrained · MANE · 25 kb · p 0.01 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0251% Admixed American · 15/59,658 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.0134% 215/1,610,074 alleles · ultra-rare exomes 200/1,457,782 · genomes 15/152,292 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0251%	3,977
European (non-Finnish)	0.0165%	6,069
Remaining individualsnot grpmax-eligible	0.00642%	15,582
African / African-American	0.00267%	37,488

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.Ala2Val
Coding: c.5C>T
MANE Select: NM_015959
Type: single nucleotide variant
Location: chr11:57712623 (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.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
TMX2 p.Arg111Pro 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-ala2val (accessed [today's date]).

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