Is TPM3 p.Ala79Pro (c.235G>C) pathogenic?

TPM3 p.Ala79Pro (c.235G>C) is classified Uncertain significance in TPM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: likely pathogenic (0.9913); Very rare (popmax 8.47e-05%, nfe); Associated with congenital myopathy 4B, autosomal recessive.

What condition is associated with TPM3 p.Ala79Pro (c.235G>C)?

TPM3 p.Ala79Pro (c.235G>C) is associated with congenital myopathy 4B, autosomal recessive, congenital fiber-type disproportion myopathy (ClinVar).

How common is TPM3 p.Ala79Pro (c.235G>C) in the general population?

TPM3 p.Ala79Pro (c.235G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Intermediate nemaline 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.Ala79Pro (c.235G>C)?

AlphaMissense predicts likely pathogenic (score 0.9913) — an in-silico prediction, not a clinical call.

TPM3 p.Ala79Pro

c.235G>C · rs1663665111 · VCV2062997

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9913 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myopathy 4B, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.9913	likely pathogenic · top 6% in TPM3
REVEL	0.735	pathogenic-leaning
SaProt	LLR -11.95	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 7.7	phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 19 kb · p 4.4e-08 · regional, not allelic
Overall
CADD	27.4	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.2e-05% 1/1,614,148 alleles · very rare exomes 1/1,461,884 · genomes 0/152,264 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TPM3
Protein: p.Ala79Pro
Coding: c.235G>C
MANE Select: NM_152263
dbSNP: rs1663665111
Type: single nucleotide variant
Location: chr1:154191194 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 91.69 · 1 PDB
Residue 79: an α-helix

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

Disease context

congenital myopathy 4B, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital fiber-type disproportion myopathy

For Intermediate nemaline myopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

TPM3 p.Ala79Val Uncertain significance ★ same residue
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

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-ala79pro (accessed [today's date]).

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