Is TPM3 p.Ser246= (c.738G>A) pathogenic?

TPM3 p.Ser246= (c.738G>A) is classified Likely benign in TPM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-27). Ultra-rare (popmax 0.033%, mid); Associated with congenital myopathy 4B, autosomal recessive.

What condition is associated with TPM3 p.Ser246= (c.738G>A)?

TPM3 p.Ser246= (c.738G>A) is associated with congenital myopathy 4B, autosomal recessive, congenital fiber-type disproportion myopathy (ClinVar).

How common is TPM3 p.Ser246= (c.738G>A) in the general population?

TPM3 p.Ser246= (c.738G>A) is ultra-rare (popmax 0.033%, mid) (gnomAD).

How is Intermediate nemaline myopathy inherited?

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

TPM3 p.Ser246=

c.738G>A · VCV4788380

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

congenital myopathy 4B, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.1
Overall
CADD	7.838	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000616% 9/1,461,872 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0048%	20,837
Admixed American	0.00167%	60,020
European (non-Finnish)	0.000254%	393,340

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.Ser246=
Coding: c.738G>A
MANE Select: NM_152263
Type: single nucleotide variant
Location: chr1:154170437 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 91.69 · 1 PDB

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.Ser246Leu 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-ser246 (accessed [today's date]).

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