Is TCAP p.Pro84His (c.251C>A) pathogenic?

TCAP p.Pro84His (c.251C>A) is classified Uncertain significance in TCAP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-29). AlphaMissense: likely pathogenic (0.7326); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with TCAP p.Pro84His (c.251C>A)?

TCAP p.Pro84His (c.251C>A) is associated with Cardiovascular phenotype (ClinVar).

How common is TCAP p.Pro84His (c.251C>A) in the general population?

TCAP p.Pro84His (c.251C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TCAP p.Pro84His (c.251C>A)?

AlphaMissense predicts likely pathogenic (score 0.7326) — an in-silico prediction, not a clinical call.

TCAP p.Pro84His

c.251C>A · VCV3966363

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7326 · 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	0.7326	likely pathogenic · top 6% in TCAP
REVEL	0.747	pathogenic-leaning
SaProt	LLR -12.68	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 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 746 bp · p 0.44 · regional, not allelic
Overall
CADD	24.3	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: TCAP
Protein: p.Pro84His
Coding: c.251C>A
MANE Select: NM_003673
Type: single nucleotide variant
Location: chr17:39665856 (GRCh38)
Gene constraint: LOEUF 1.374 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.89 · 2 PDB
Residue 84: a β-strand

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

Similar variants

TCAP p.Pro84= Likely benign ★ same residue
TCAP p.Gln53Ter Pathogenic/Likely pathogenic ★★ same condition
TCAP c.110+4A>G Uncertain significance ★★ same condition
TCAP p.Arg130His Uncertain significance ★★ ⚠ same condition
TCAP p.Arg153Ser Uncertain significance ★★ ⚠ same condition
TCAP p.Arg154Cys Uncertain significance ★★ ⚠ same condition
TCAP p.Arg154Ser Uncertain significance ★★ same condition
TCAP p.Arg158Gly 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-pro84his (accessed [today's date]).

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