Is TGM2 p.Pro587Ser (c.1759C>T) pathogenic?

TGM2 p.Pro587Ser (c.1759C>T) is classified Uncertain significance in TGM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely pathogenic (0.6993); Absent from gnomAD v4.1.

How common is TGM2 p.Pro587Ser (c.1759C>T) in the general population?

TGM2 p.Pro587Ser (c.1759C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TGM2 p.Pro587Ser (c.1759C>T)?

AlphaMissense predicts likely pathogenic (score 0.6993) — an in-silico prediction, not a clinical call.

TGM2 p.Pro587Ser

c.1759C>T · VCV4183673

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6993	likely pathogenic
REVEL	0.803	moderately pathogenic-leaning
SaProt	LLR -12.63	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 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 35 kb · p 0.0045 · regional, not allelic
Overall
CADD	28.9	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: TGM2
Protein: p.Pro587Ser
Coding: c.1759C>T
MANE Select: NM_004613
Type: single nucleotide variant
Location: chr20:38132357 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.91 · 14 PDB
Residue 587: an α-helix

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-pro587ser (accessed [today's date]).

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