Is TCAP p.Val59Met (c.175G>A) pathogenic?

TCAP p.Val59Met (c.175G>A) is classified Uncertain significance in TCAP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-17). AlphaMissense: likely benign (0.1266); Very rare (popmax 0.000594%, nfe); Associated with familial hypertrophic cardiomyopathy.

What condition is associated with TCAP p.Val59Met (c.175G>A)?

TCAP p.Val59Met (c.175G>A) is associated with familial hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 25 (ClinVar).

How common is TCAP p.Val59Met (c.175G>A) in the general population?

TCAP p.Val59Met (c.175G>A) is very rare (popmax 0.000594%, nfe) (gnomAD).

What do computational predictors say about TCAP p.Val59Met (c.175G>A)?

AlphaMissense predicts likely benign (score 0.1266) — an in-silico prediction, not a clinical call.

TCAP p.Val59Met

c.175G>A · rs1064796829 · VCV424154

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1266 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000594%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hypertrophic cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.1266	likely benign
REVEL	0.252	benign-leaning
SaProt	LLR -7.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 746 bp · p 0.44 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.000594% European (non-Finnish) · 7/1,178,428 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000435% 7/1,609,486 alleles · very rare exomes 5/1,457,296 · genomes 2/152,190 · joint denominator

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: TCAP
Protein: p.Val59Met
Coding: c.175G>A
MANE Select: NM_003673
dbSNP: rs1064796829
Type: single nucleotide variant
Location: chr17:39665780 (GRCh38)
Gene constraint: LOEUF 1.374 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.89 · 2 PDB
Residue 59: a β-strand

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

Disease context

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

Also linked: hypertrophic cardiomyopathy 25

Similar variants

TCAP p.Cys57Ter Pathogenic/Likely pathogenic ★★ same condition
TCAP p.Gln53Ter Pathogenic/Likely pathogenic ★★ same condition
TCAP p.Glu35Ter Pathogenic ★★ same condition
TCAP p.Trp22Ter Pathogenic/Likely pathogenic ★★ same condition
TCAP p.Trp25Ter Pathogenic/Likely pathogenic ★★ same condition
TCAP c.110+4A>G Uncertain significance ★★ same condition
TCAP c.*292G>A Uncertain significance ★★ same condition
TCAP c.*297C>T Uncertain significance ★★ 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/tcap-p-val59met (accessed [today's date]).

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