Is TPM2 p.Ser61Pro (c.181T>C) pathogenic?

TPM2 p.Ser61Pro (c.181T>C) is classified Conflicting classifications of pathogenicity in TPM2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2021-05-08). AlphaMissense: likely pathogenic (0.9707); Absent from gnomAD v4.1; Associated with arthrogryposis, distal, type 1A.

What condition is associated with TPM2 p.Ser61Pro (c.181T>C)?

TPM2 p.Ser61Pro (c.181T>C) is associated with arthrogryposis, distal, type 1A, congenital myopathy 23 (ClinVar).

How common is TPM2 p.Ser61Pro (c.181T>C) in the general population?

TPM2 p.Ser61Pro (c.181T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TPM2 p.Ser61Pro (c.181T>C)?

AlphaMissense predicts likely pathogenic (score 0.9707) — an in-silico prediction, not a clinical call.

TPM2 p.Ser61Pro

c.181T>C · rs878854363 · VCV224658

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9707 · 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	0.9707	likely pathogenic
REVEL	0.775	moderately pathogenic-leaning
SaProt	LLR -14.14	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 11	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	32.0	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

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.Ser61Pro
Coding: c.181T>C
MANE Select: NM_003289
dbSNP: rs878854363
Type: single nucleotide variant
Location: chr9:35689205 (GRCh38)
Gene constraint: LOEUF 0.87 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 91.51
Residue 61: the 'disordered' region; a modified residue (phosphoserine; by pik3cg)

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-ser61pro (accessed [today's date]).

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