Is TGM2 p.Ala511Val (c.1532C>T) pathogenic?

TGM2 p.Ala511Val (c.1532C>T) is classified Uncertain significance in TGM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-18). AlphaMissense: ambiguous (0.4047); Very rare (popmax 0.00267%, afr).

How common is TGM2 p.Ala511Val (c.1532C>T) in the general population?

TGM2 p.Ala511Val (c.1532C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about TGM2 p.Ala511Val (c.1532C>T)?

AlphaMissense predicts ambiguous (score 0.4047) — an in-silico prediction, not a clinical call.

TGM2 p.Ala511Val

c.1532C>T · VCV4594580

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4047 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Computational evidence

Protein change
AlphaMissense	0.4047	ambiguous
REVEL	0.293	indeterminate
SaProt	LLR -10.53	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 35 kb · p 0.0045 · regional, not allelic
Overall
CADD	28.4	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 0.00267% African / African-American · 2/74,854 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.00087% 14/1,608,814 alleles · very rare exomes 11/1,456,614 · genomes 3/152,200 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,427
Admixed American	0.00169%	59,106
Remaining individualsnot grpmax-eligible	0.00161%	62,298
European (non-Finnish)	0.000849%	117,766

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: TGM2
Protein: p.Ala511Val
Coding: c.1532C>T
MANE Select: NM_004613
Type: single nucleotide variant
Location: chr20:38138196 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.91 · 14 PDB
Residue 511: a β-strand

Full TGM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TGM2 c.433+3G>A Likely benign ★★ same type
TGM2 p.Ala282= Benign ★★ same type
TGM2 p.Ala390= Benign ★★ same type
TGM2 p.Arg28= Benign ★★ same type
TGM2 p.Arg377His Benign ★★ ⚠ same type
TGM2 p.Arg76His Benign ★★ same type
TGM2 p.Asp326= Benign ★★ same type
TGM2 p.Ile416= 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/tgm2-p-ala511val (accessed [today's date]).

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