Is TPM3 p.Arg91Cys (c.271C>T) pathogenic?

TPM3 p.Arg91Cys (c.271C>T) is classified Pathogenic/Likely pathogenic in TPM3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-30). AlphaMissense: likely pathogenic (0.9931); Absent from gnomAD v4.1; Associated with congenital myopathy 4B, autosomal recessive.

What condition is associated with TPM3 p.Arg91Cys (c.271C>T)?

TPM3 p.Arg91Cys (c.271C>T) is associated with congenital myopathy 4B, autosomal recessive, congenital fiber-type disproportion myopathy, congenital myopathy 4A, autosomal dominant (ClinVar).

How common is TPM3 p.Arg91Cys (c.271C>T) in the general population?

TPM3 p.Arg91Cys (c.271C>T) is absent from gnomAD v4.1 (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.Arg91Cys (c.271C>T)?

AlphaMissense predicts likely pathogenic (score 0.9931) — an in-silico prediction, not a clinical call.

TPM3 p.Arg91Cys

c.271C>T · rs1571418855 · VCV652762

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9931 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myopathy 4B, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.9931	likely pathogenic ✓ concordant with ClinVar · top 5% in TPM3
REVEL	0.916	moderately pathogenic-leaning
SaProt	LLR -13.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.50 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 19 kb · p 4.4e-08 · regional, not allelic
Overall
CADD	34.0	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: TPM3
Protein: p.Arg91Cys
Coding: c.271C>T
MANE Select: NM_152263
dbSNP: rs1571418855
Type: single nucleotide variant
Location: chr1:154176221 (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 myopathy 4B, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital fiber-type disproportion myopathy congenital myopathy 4A, autosomal dominant

For Intermediate nemaline myopathy (Orphanet):

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

Similar variants

TPM3 p.Arg91His Likely pathogenic ★★ same residue
TPM3 p.Arg91Gly Likely pathogenic ★ same residue
TPM3 p.Arg91Pro Pathogenic ★ same residue
TPM3 p.Arg91= Likely benign ★ 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-arg91cys (accessed [today's date]).

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