Is TCAP p.Arg130Ser (c.388C>A) pathogenic?

TCAP p.Arg130Ser (c.388C>A) is classified Uncertain significance in TCAP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-13). AlphaMissense: ambiguous (0.5187); Ultra-rare (popmax 0.016%, afr); Associated with familial hypertrophic cardiomyopathy.

What condition is associated with TCAP p.Arg130Ser (c.388C>A)?

TCAP p.Arg130Ser (c.388C>A) is associated with familial hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 25 (ClinVar).

How common is TCAP p.Arg130Ser (c.388C>A) in the general population?

TCAP p.Arg130Ser (c.388C>A) is ultra-rare (popmax 0.016%, afr) (gnomAD).

What do computational predictors say about TCAP p.Arg130Ser (c.388C>A)?

AlphaMissense predicts ambiguous (score 0.5187) — an in-silico prediction, not a clinical call.

TCAP p.Arg130Ser

c.388C>A · rs374886575 · VCV179714

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5187 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Conditions

familial hypertrophic cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.5187	ambiguous
REVEL	0.528	indeterminate
SaProt	LLR -6.24	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 746 bp · p 0.44 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.016% African / African-American · 12/75,042 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00721%

Overall 0.000744% 12/1,612,600 alleles · ultra-rare exomes 12/1,460,302 · genomes 0/152,298 · 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.Arg130Ser
Coding: c.388C>A
MANE Select: NM_003673
dbSNP: rs374886575
Type: single nucleotide variant
Location: chr17:39665993 (GRCh38)
Gene constraint: LOEUF 1.374 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.89 · 2 PDB

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.Arg130Cys Uncertain significance ★★ ⚠ same residue
TCAP p.Arg130His Uncertain significance ★★ ⚠ same residue
TCAP p.Arg130Pro Uncertain significance ★ same residue
TCAP p.Arg130= Likely benign ★ same residue
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

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-arg130ser (accessed [today's date]).

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