Is TPM3 p.Arg91= (c.273T>C) pathogenic?

TPM3 p.Arg91= (c.273T>C) is classified Likely benign in TPM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-27). Very rare (popmax 0.000124%); Associated with congenital fiber-type disproportion myopathy.

What condition is associated with TPM3 p.Arg91= (c.273T>C)?

TPM3 p.Arg91= (c.273T>C) is associated with congenital fiber-type disproportion myopathy, congenital myopathy 4B, autosomal recessive (ClinVar).

How common is TPM3 p.Arg91= (c.273T>C) in the general population?

TPM3 p.Arg91= (c.273T>C) is very rare (popmax 0.000124%) (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.

TPM3 p.Arg91=

c.273T>C · rs974189739 · VCV758637

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000124%)

Conditions

congenital fiber-type disproportion myopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.51 · evaluated, not missing
Constraint at this position
Conservation	phyloP -2.7
Overall
CADD	3.21	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000124%

Overall 0.000124% 2/1,614,082 alleles · very rare exomes 2/1,461,878 · genomes 0/152,204 · 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.Arg91=
Coding: c.273T>C
MANE Select: NM_152263
dbSNP: rs974189739
Type: single nucleotide variant
Location: chr1:154176219 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 91.69 · 1 PDB
Residue 91: a UniProt-annotated variant site (found in patients with undefined congenital myopathy; likely pathogenic); a UniProt-annotated variant site (in cmyo4a); an α-helix

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 p.Arg91Cys Pathogenic/Likely pathogenic ★★ same residue
TPM3 p.Arg91His Likely pathogenic ★★ same residue
TPM3 p.Arg91Gly Likely pathogenic ★ same residue
TPM3 p.Arg91Pro Pathogenic ★ 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

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-arg91 (accessed [today's date]).

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