Is TGM6 p.Trp330Cys (c.990G>C) pathogenic?

TGM6 p.Trp330Cys (c.990G>C) is classified Uncertain significance in TGM6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-27). AlphaMissense: likely pathogenic (0.9952); Ultra-rare (popmax 0.045%, amr).

How common is TGM6 p.Trp330Cys (c.990G>C) in the general population?

TGM6 p.Trp330Cys (c.990G>C) is ultra-rare (popmax 0.045%, amr) (gnomAD).

What do computational predictors say about TGM6 p.Trp330Cys (c.990G>C)?

AlphaMissense predicts likely pathogenic (score 0.9952) — an in-silico prediction, not a clinical call.

TGM6 p.Trp330Cys

c.990G>C · rs764750878 · VCV2697758

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9952 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.045%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9952	likely pathogenic · top 1% in TGM6
REVEL	0.909	moderately pathogenic-leaning
SaProt	LLR -14.96	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.49	acceptor loss · deltas
Pangolin	Δ0.38	loss · gain 0.21 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 52 kb · p 0.37 · regional, not allelic
Overall
CADD	33.0	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 0.045% Admixed American · 27/59,986 alleles

Filtering AF 0.0317% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0273%

Overall 0.00186% 30/1,613,990 alleles · ultra-rare exomes 28/1,461,872 · genomes 2/152,118 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.045%	2,222
Remaining individualsnot grpmax-eligible	0.0048%	20,829

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: TGM6
Protein: p.Trp330Cys
Coding: c.990G>C
MANE Select: NM_198994
dbSNP: rs764750878
Type: single nucleotide variant
Location: chr20:2403397 (GRCh38)
Gene constraint: LOEUF 1.134 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.95

Full TGM6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TGM6 c.1678+1G>A Uncertain significance ★★ same type
TGM6 c.1967+1G>A Uncertain significance ★★ same type
TGM6 c.543+1G>T Uncertain significance ★★ same type
TGM6 c.851-2A>C Uncertain significance ★★ same type
TGM6 c.990-1G>C Uncertain significance ★★ same type
TGM6 p.Ala174Ser Uncertain significance ★★ ⚠ same type
TGM6 p.Ala341Thr Uncertain significance ★★ ⚠ same type
TGM6 p.Ala393= Uncertain significance ★★ 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/tgm6-p-trp330cys (accessed [today's date]).

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