Is TPM1 p.Ala151= (c.453C>A) pathogenic?

TPM1 p.Ala151= (c.453C>A) is classified Benign in TPM1 (ClinVar, Multiple submitters, 22 submitters; last evaluated 2026-02-04). Common (popmax 95.2%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with TPM1 p.Ala151= (c.453C>A)?

TPM1 p.Ala151= (c.453C>A) is associated with Cardiovascular phenotype, cardiomyopathy, hypertrophic cardiomyopathy (ClinVar).

TPM1 p.Ala151=

Q: How common is TPM1 p.Ala151= (c.453C>A) in the general population?

TPM1 p.Ala151= (c.453C>A) is common (popmax 95.2%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.453C>A · rs1071646 · VCV31888

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 22 submitters

gnomAD v4.1

Common

common (popmax 95.2%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

Cardiovascular phenotype

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 0.21	GERP -0.31, phastCons 0.97
Overall
CADD	11.61	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 95.2% East Asian · 42,596/44,762 alleles

Filtering AF 94.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 94.1%

Overall 66.4% 1,069,035/1,610,730 alleles · common exomes 969,963/1,458,728 · genomes 99,072/152,002 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	95.2%	1
Amishnot grpmax-eligible	74.1%	1
South Asian	70.4%	1
Finnishnot grpmax-eligible	69.8%	1
Remaining individualsnot grpmax-eligible	67.3%	1
Ashkenazi Jewishnot grpmax-eligible	66.3%	2
European (non-Finnish)	65.6%	2
African / African-American	61.4%	2
Middle Eastern	59.7%	2
Admixed American	56.6%	2

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.Ala151=
Coding: c.453C>A
MANE Select: NM_001018005
dbSNP: rs1071646
Type: single nucleotide variant
Location: chr15:63059641 (GRCh38)
Gene constraint: LOEUF 0.757 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.67 · 14 PDB
Residue 151: an α-helix

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

Disease context

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

Also linked: cardiomyopathy hypertrophic cardiomyopathy hypertrophic cardiomyopathy 3 hypertrophic cardiomyopathy 1 dilated cardiomyopathy 1Y

Similar variants

TPM1 p.Ala151Thr Uncertain significance ★ ⚠ same residue
TPM1 p.Ala183Val Uncertain significance ★★★ ⚠ same condition
TPM1 p.Met281Thr Uncertain significance ★★★ ⚠ same condition
TPM1 p.Thr108Ile Uncertain significance ★★★ ⚠ same condition
TPM1 p.Lys266Arg Likely benign ★★★ ⚠ same condition
TPM1 p.Thr282Ser Benign ★★★ same condition
TPM1 p.Ala63Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
TPM1 p.Arg160His 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/tpm1-p-ala151 (accessed [today's date]).

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