Is TRIM63 p.Ile130Met (c.390C>G) pathogenic?

TRIM63 p.Ile130Met (c.390C>G) is classified Conflicting classifications of pathogenicity in TRIM63 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-08-15). AlphaMissense: ambiguous (0.3544); Rare (popmax 0.264%, mid); Associated with hypertrophic cardiomyopathy.

What condition is associated with TRIM63 p.Ile130Met (c.390C>G)?

TRIM63 p.Ile130Met (c.390C>G) is associated with hypertrophic cardiomyopathy (ClinVar).

How common is TRIM63 p.Ile130Met (c.390C>G) in the general population?

TRIM63 p.Ile130Met (c.390C>G) is rare (popmax 0.264%, mid) (gnomAD).

What do computational predictors say about TRIM63 p.Ile130Met (c.390C>G)?

AlphaMissense predicts ambiguous (score 0.3544) — an in-silico prediction, not a clinical call.

TRIM63 p.Ile130Met

c.390C>G · rs377334933 · VCV978746

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3544 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.264%, mid)

Conditions

hypertrophic cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.3544	ambiguous
REVEL	0.37	indeterminate
SaProt	LLR -11.92	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 16 kb · p 0.51 · regional, not allelic
Overall
CADD	25.5	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 0.264% Middle Eastern · 16/6,062 alleles

Filtering AF 0.165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.135%

Overall 0.00601% 97/1,614,200 alleles · rare exomes 90/1,461,866 · genomes 7/152,334 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.264%	379
Remaining individualsnot grpmax-eligible	0.0112%	8,930
European (non-Finnish)	0.00585%	17,102
South Asian	0.00439%	22,770
African / African-American	0.00133%	75,056

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.Ile130Met
Coding: c.390C>G
MANE Select: NM_032588
dbSNP: rs377334933
Type: single nucleotide variant
Location: chr1:26061277 (GRCh38)
Gene constraint: LOEUF 1.329 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.88 · 3 PDB
Residue 130: a UniProt-annotated variant site (in cmh31; uncertain significance; decreased function in protein ubiquitination; decreased z line localization); the 'interaction with ttn' region

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

Disease context

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

Similar variants

TRIM63 p.Arg112Gln Uncertain significance ★★ ⚠ same condition
TRIM63 c.1051+1G>A Uncertain significance ★ same condition
TRIM63 p.Arg74Cys Uncertain significance ★ ⚠ same condition
TRIM63 p.Cys145Tyr Conflicting classifications of pathogenicity ★ ⚠ same condition
TRIM63 p.Cys23Tyr Uncertain significance ★ ⚠ same condition
TRIM63 p.Cys39Gly Uncertain significance ★ ⚠ same condition
TRIM63 p.Cys75Tyr Conflicting classifications of pathogenicity ★ ⚠ same condition
TRIM63 p.Gln247Ter Conflicting classifications of pathogenicity ★ 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/trim63-p-ile130met (accessed [today's date]).

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