Is TPM3 p.Ser88Pro (c.262T>C) pathogenic?

TPM3 p.Ser88Pro (c.262T>C) is classified Uncertain significance in TPM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-09-01). AlphaMissense: likely pathogenic (0.9883); Absent from gnomAD v4.1; Associated with congenital fiber-type disproportion myopathy.

What condition is associated with TPM3 p.Ser88Pro (c.262T>C)?

TPM3 p.Ser88Pro (c.262T>C) is associated with congenital fiber-type disproportion myopathy, congenital myopathy 4B, autosomal recessive (ClinVar).

How common is TPM3 p.Ser88Pro (c.262T>C) in the general population?

TPM3 p.Ser88Pro (c.262T>C) is absent from gnomAD v4.1 (gnomAD).

How is Congenital fiber-type disproportion myopathy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TPM3 p.Ser88Pro (c.262T>C)?

AlphaMissense predicts likely pathogenic (score 0.9883) — an in-silico prediction, not a clinical call.

TPM3 p.Ser88Pro

c.262T>C · rs1558052214 · VCV561134

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9883 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital fiber-type disproportion myopathy

Computational evidence

Protein change
AlphaMissense	0.9883	likely pathogenic · top 8% in TPM3
REVEL	0.924	moderately pathogenic-leaning
SaProt	LLR -12.80	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.4	phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 19 kb · p 4.4e-08 · regional, not allelic
Overall
CADD	29.4	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: TPM3
Protein: p.Ser88Pro
Coding: c.262T>C
MANE Select: NM_152263
dbSNP: rs1558052214
Type: single nucleotide variant
Location: chr1:154176230 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 91.69 · 1 PDB
Residue 88: a UniProt-annotated variant site (in cmyo4a); an α-helix; a modified residue (phosphoserine)

Full TPM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital fiber-type disproportion myopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myopathy 4B, autosomal recessive

For Congenital fiber-type disproportion myopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

TPM3 c.118-12G>A Pathogenic/Likely pathogenic ★★ same condition
TPM3 p.Ala152Val Pathogenic/Likely pathogenic ★★ same condition
TPM3 p.Arg168Cys Pathogenic ★★ same condition
TPM3 p.Arg168Gly Pathogenic/Likely pathogenic ★★ same condition
TPM3 p.Arg168His Pathogenic ★★ same condition
TPM3 p.Arg91Cys Pathogenic/Likely pathogenic ★★ same condition
TPM3 p.Arg91His Likely pathogenic ★★ same condition
TPM3 p.Gln32Ter Pathogenic ★★ 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/tpm3-p-ser88pro (accessed [today's date]).

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