Is TCAP p.Arg153Cys (c.457C>T) pathogenic?

TCAP p.Arg153Cys (c.457C>T) is classified Uncertain significance in TCAP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.082); Very rare (popmax 0.00267%, afr); Associated with hypertrophic cardiomyopathy 25.

What condition is associated with TCAP p.Arg153Cys (c.457C>T)?

TCAP p.Arg153Cys (c.457C>T) is associated with hypertrophic cardiomyopathy 25, familial hypertrophic cardiomyopathy (ClinVar).

How common is TCAP p.Arg153Cys (c.457C>T) in the general population?

TCAP p.Arg153Cys (c.457C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about TCAP p.Arg153Cys (c.457C>T)?

AlphaMissense predicts likely benign (score 0.082) — an in-silico prediction, not a clinical call.

TCAP p.Arg153Cys

c.457C>T · rs761498487 · VCV1810044

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.082 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypertrophic cardiomyopathy 25

Computational evidence

Protein change
AlphaMissense	0.082	likely benign
REVEL	0.247	benign-leaning
SaProt	LLR -8.62	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 3.4	GERP 1.6, phastCons 0.35
Regional constraint	o/e 0.95	unconstrained · MANE · 746 bp · p 0.44 · regional, not allelic
Overall
CADD	23.4	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 0.00267% African / African-American · 2/74,920 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00175% 28/1,604,524 alleles · very rare exomes 23/1,452,316 · genomes 5/152,208 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,460
East Asian	0.00223%	44,888
European (non-Finnish)	0.00195%	51,301
Remaining individualsnot grpmax-eligible	0.0016%	62,414
South Asian	0.0011%	91,080

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.Arg153Cys
Coding: c.457C>T
MANE Select: NM_003673
dbSNP: rs761498487
Type: single nucleotide variant
Location: chr17:39666062 (GRCh38)
Gene constraint: LOEUF 1.374 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.89 · 2 PDB
Residue 153: the 'disordered' region; a UniProt-annotated variant site (in cmh25)

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

Disease context

hypertrophic cardiomyopathy 25 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypertrophic cardiomyopathy

Similar variants

TCAP p.Arg153Ser Uncertain significance ★★ ⚠ same residue
TCAP p.Arg153His Conflicting classifications of pathogenicity ★ ⚠ same residue
TCAP p.Arg153Pro Uncertain significance ★ ⚠ same residue
TCAP p.Arg153fs Uncertain significance ★ 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-arg153cys (accessed [today's date]).

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