Is TPM2 p.Gln147Pro (c.440A>C) pathogenic?

TPM2 p.Gln147Pro (c.440A>C) is classified Uncertain significance in TPM2 (ClinVar, Single submitter, 3 submitters; last evaluated 2024-06-19). AlphaMissense: likely pathogenic (0.9934); Absent from gnomAD v4.1; Associated with arthrogryposis, distal, type 1A.

What condition is associated with TPM2 p.Gln147Pro (c.440A>C)?

TPM2 p.Gln147Pro (c.440A>C) is associated with arthrogryposis, distal, type 1A, congenital myopathy 23 (ClinVar).

How common is TPM2 p.Gln147Pro (c.440A>C) in the general population?

TPM2 p.Gln147Pro (c.440A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TPM2 p.Gln147Pro (c.440A>C)?

AlphaMissense predicts likely pathogenic (score 0.9934) — an in-silico prediction, not a clinical call.

TPM2 p.Gln147Pro

c.440A>C · rs104894128 · VCV12461

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9934 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

arthrogryposis, distal, type 1A

Computational evidence

Protein change
AlphaMissense	0.9934	likely pathogenic · top 6% in TPM2
REVEL	0.926	moderately pathogenic-leaning
SaProt	LLR -14.22	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 1.9, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 6,655 bp · p 4.5e-19 · regional, not allelic
Overall
CADD	31.0	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

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: TPM2
Protein: p.Gln147Pro
Coding: c.440A>C
MANE Select: NM_003289
dbSNP: rs104894128
Type: single nucleotide variant
Location: chr9:35685486 (GRCh38)
Gene constraint: LOEUF 0.87 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 91.51
Residue 147: a UniProt-annotated variant site (in cmyo23)

Full TPM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

arthrogryposis, distal, type 1A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myopathy 23

Similar variants

TPM2 p.Ala155Thr Pathogenic/Likely pathogenic ★★ same condition
TPM2 p.Arg133Trp Pathogenic ★★ same condition
TPM2 p.Gln24Ter Pathogenic/Likely pathogenic ★★ same condition
TPM2 p.Gln9Pro Likely pathogenic ★★ same condition
TPM2 p.Glu117Lys Pathogenic/Likely pathogenic ★★ same condition
TPM2 p.Lys128Glu Likely pathogenic ★★ same condition
TPM2 p.Tyr261Cys Pathogenic/Likely pathogenic ★★ same condition
TPM2 c.240+5G>T 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/tpm2-p-gln147pro (accessed [today's date]).

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