Is TPM1 p.Arg35= (c.103A>C) pathogenic?

TPM1 p.Arg35= (c.103A>C) is classified Likely benign in TPM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-23). Very rare (popmax 8.52e-05%, nfe); Associated with cardiomyopathy.

What condition is associated with TPM1 p.Arg35= (c.103A>C)?

TPM1 p.Arg35= (c.103A>C) is associated with cardiomyopathy (ClinVar).

How common is TPM1 p.Arg35= (c.103A>C) in the general population?

TPM1 p.Arg35= (c.103A>C) is very rare (popmax 8.52e-05%, nfe) (gnomAD).

TPM1 p.Arg35=

c.103A>C · rs1596297347 · VCV2774663

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.52e-05%, nfe)

Conditions

cardiomyopathy

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 -0.43	GERP -3.7, phastCons 0.004
Overall
CADD	11.95	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.52e-05% European (non-Finnish) · 1/1,173,396 alleles

Overall 0.000657% 1/152,218 alleles · very rare

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: TPM1
Protein: p.Arg35=
Coding: c.103A>C
MANE Select: NM_001018005
dbSNP: rs1596297347
Type: single nucleotide variant
Location: chr15:63042932 (GRCh38)
Gene constraint: LOEUF 0.757 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.67 · 14 PDB
Residue 35: the 'disordered' region

Full TPM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TPM1 p.Arg35Lys Uncertain significance ★★ ⚠ same residue
TPM1 p.Arg35Ser Uncertain significance ★ same residue
TPM1 p.Arg35Thr Uncertain significance ★★ ⚠ same residue
TPM1 p.Arg35Gly Uncertain significance ★ ⚠ same residue
TPM1 p.Ala183Val Uncertain significance ★★★ ⚠ same condition
TPM1 p.Met281Thr Uncertain significance ★★★ ⚠ same condition
TPM1 p.Lys266Arg Likely benign ★★★ ⚠ same condition
TPM1 p.Thr282Ser Benign ★★★ 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/tpm1-p-arg35 (accessed [today's date]).

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