Is TPM1 p.Ile172Phe (c.514A>T) pathogenic?

TPM1 p.Ile172Phe (c.514A>T) is classified Uncertain significance in TPM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-03-16). AlphaMissense: likely pathogenic (0.663); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with TPM1 p.Ile172Phe (c.514A>T)?

TPM1 p.Ile172Phe (c.514A>T) is associated with Cardiovascular phenotype (ClinVar).

How common is TPM1 p.Ile172Phe (c.514A>T) in the general population?

TPM1 p.Ile172Phe (c.514A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TPM1 p.Ile172Phe (c.514A>T)?

AlphaMissense predicts likely pathogenic (score 0.663) — an in-silico prediction, not a clinical call.

TPM1 p.Ile172Phe

c.514A>T · rs760374266 · VCV520273

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.663 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.663	likely pathogenic
REVEL	0.887	moderately pathogenic-leaning
SaProt	LLR -12.95	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 19 kb · p 2.5e-23 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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: TPM1
Protein: p.Ile172Phe
Coding: c.514A>T
MANE Select: NM_001018005
dbSNP: rs760374266
Type: single nucleotide variant
Location: chr15:63060890 (GRCh38)
Gene constraint: LOEUF 0.757 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.67 · 14 PDB
Residue 172: 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

Similar variants

TPM1 p.Ile172Met Uncertain significance ★★ ⚠ same residue
TPM1 p.Ile172Asn Uncertain significance ★ ⚠ same residue
TPM1 p.Ile172Leu Uncertain significance ★ ⚠ same residue
TPM1 p.Ile172Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
TPM1 p.Asp175Asn Pathogenic ★★ same condition
TPM1 p.Glu62Gln Likely pathogenic ★★ ⚠ same condition
TPM1 p.Ser215Leu Pathogenic/Likely pathogenic ★★ same condition
TPM1 p.Val95Ala 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-ile172phe (accessed [today's date]).

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