Is TGM6 p.Phe136Ser (c.407T>C) pathogenic?

TGM6 p.Phe136Ser (c.407T>C) is classified Uncertain significance in TGM6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-23). AlphaMissense: likely pathogenic (0.9056); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TGM6 p.Phe136Ser (c.407T>C)?

TGM6 p.Phe136Ser (c.407T>C) is associated with Inborn genetic diseases (ClinVar).

How common is TGM6 p.Phe136Ser (c.407T>C) in the general population?

TGM6 p.Phe136Ser (c.407T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TGM6 p.Phe136Ser (c.407T>C)?

AlphaMissense predicts likely pathogenic (score 0.9056) — an in-silico prediction, not a clinical call.

TGM6 p.Phe136Ser

c.407T>C · VCV4183726

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9056 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9056	likely pathogenic
REVEL	0.918	moderately pathogenic-leaning
SaProt	LLR -11.20	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.6, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 52 kb · p 0.37 · regional, not allelic
Overall
CADD	26.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TGM6
Protein: p.Phe136Ser
Coding: c.407T>C
MANE Select: NM_198994
Type: single nucleotide variant
Location: chr20:2395419 (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

Disease context

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

Similar variants

TGM6 p.Phe136Tyr Uncertain significance ★ ⚠ same residue
TGM6 p.Arg13Trp Uncertain significance ★★ ⚠ same condition
TGM6 p.Arg410Gln Uncertain significance ★★ ⚠ same condition
TGM6 p.Arg410Trp Uncertain significance ★★ ⚠ same condition
TGM6 p.Arg448Gln Uncertain significance ★★ ⚠ same condition
TGM6 p.Arg474Cys Uncertain significance ★★ ⚠ same condition
TGM6 p.Arg523Gln Uncertain significance ★★ ⚠ same condition
TGM6 p.Arg526Gly 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/tgm6-p-phe136ser (accessed [today's date]).

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