Is TRIM63 p.Leu319Pro (c.956T>C) pathogenic?

TRIM63 p.Leu319Pro (c.956T>C) is classified Pathogenic in TRIM63 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-07-18). AlphaMissense: likely pathogenic (0.9852); Ultra-rare (popmax 0.045%, amr); Associated with cardiomyopathy, familial hypertrophic, 31.

What condition is associated with TRIM63 p.Leu319Pro (c.956T>C)?

TRIM63 p.Leu319Pro (c.956T>C) is associated with cardiomyopathy, familial hypertrophic, 31 (ClinVar).

How common is TRIM63 p.Leu319Pro (c.956T>C) in the general population?

TRIM63 p.Leu319Pro (c.956T>C) is ultra-rare (popmax 0.045%, amr) (gnomAD).

What do computational predictors say about TRIM63 p.Leu319Pro (c.956T>C)?

AlphaMissense predicts likely pathogenic (score 0.9852) — an in-silico prediction, not a clinical call.

TRIM63 p.Leu319Pro

c.956T>C · VCV4057303

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9852 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.045%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cardiomyopathy, familial hypertrophic, 31

Computational evidence

Protein change
AlphaMissense	0.9852	likely pathogenic ✓ concordant with ClinVar · top 9% in TRIM63
REVEL	0.63	indeterminate
SaProt	LLR -15.97	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 16 kb · p 0.51 · regional, not allelic
Overall
CADD	25.8	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 0.045% Admixed American · 27/60,020 alleles

Filtering AF 0.0317% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0273%

Overall 0.00167% 27/1,614,160 alleles · ultra-rare exomes 27/1,461,836 · genomes 0/152,324 · 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: TRIM63
Protein: p.Leu319Pro
Coding: c.956T>C
MANE Select: NM_032588
Type: single nucleotide variant
Location: chr1:26057226 (GRCh38)
Gene constraint: LOEUF 1.329 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.88 · 3 PDB
Residue 319: the cos domain; a UniProt-annotated variant site (in cmh31; likely pathogenic; no protein detected in patient cells; loss of function in protein ubiquitination); a UniProt-annotated variant site (sequence variant); a UniProt-annotated variant site (in cmh31; uncertain significance)

Full TRIM63 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cardiomyopathy, familial hypertrophic, 31 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRIM63 p.Cys145Tyr Conflicting classifications of pathogenicity ★ ⚠ same condition
TRIM63 p.Cys23Tyr Uncertain significance ★ ⚠ same condition
TRIM63 p.Cys75Tyr Conflicting classifications of pathogenicity ★ ⚠ same condition
TRIM63 p.Gln247Ter Conflicting classifications of pathogenicity ★ same condition
TRIM63 p.Ser161fs Pathogenic ★★ same condition
TRIM63 p.Lys146fs Uncertain significance ★ same condition
TRIM63 p.Ala244Val Uncertain significance ★★ ⚠ same type
TRIM63 p.Ala289Val Uncertain significance ★★ ⚠ same type

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/trim63-p-leu319pro (accessed [today's date]).

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