Is TCAP p.Pro141Ala (c.421C>G) pathogenic?

TCAP p.Pro141Ala (c.421C>G) is classified Conflicting classifications of pathogenicity in TCAP (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-10-17). AlphaMissense: likely benign (0.2943); Very rare (popmax 0.00746%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with TCAP p.Pro141Ala (c.421C>G)?

TCAP p.Pro141Ala (c.421C>G) is associated with Cardiovascular phenotype, autosomal recessive limb-girdle muscular dystrophy type 2G, hypertrophic cardiomyopathy 25 (ClinVar).

How common is TCAP p.Pro141Ala (c.421C>G) in the general population?

TCAP p.Pro141Ala (c.421C>G) is very rare (popmax 0.00746%, nfe) (gnomAD).

What do computational predictors say about TCAP p.Pro141Ala (c.421C>G)?

AlphaMissense predicts likely benign (score 0.2943) — an in-silico prediction, not a clinical call.

TCAP p.Pro141Ala

c.421C>G · rs45509691 · VCV180535

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.2943 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00746%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2943	likely benign
REVEL	0.725	pathogenic-leaning
SaProt	LLR -8.40	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	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 0.00746% European (non-Finnish) · 88/1,179,928 alleles

Filtering AF 0.00615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00573%

Overall 0.00584% 94/1,610,684 alleles · very rare exomes 91/1,458,470 · genomes 3/152,214 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00746%	13,408
Remaining individualsnot grpmax-eligible	0.0064%	15,616
Finnishnot grpmax-eligible	0.00165%	60,766
African / African-American	0.00133%	74,944

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.Pro141Ala
Coding: c.421C>G
MANE Select: NM_003673
dbSNP: rs45509691
Type: single nucleotide variant
Location: chr17:39666026 (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

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

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2G hypertrophic cardiomyopathy 25 familial hypertrophic cardiomyopathy

Similar variants

TCAP p.Pro141= Likely benign ★★ same residue
TCAP p.Pro141Leu Uncertain significance ★ ⚠ same residue
TCAP c.110+5G>T Likely pathogenic ★★ same condition
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

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-pro141ala (accessed [today's date]).

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