Is TRIM63 p.Ile322Thr (c.965T>C) pathogenic?

TRIM63 p.Ile322Thr (c.965T>C) is classified Uncertain significance in TRIM63 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-11-26). AlphaMissense: likely benign (0.3391); Very rare (popmax 0.00801%, afr); Associated with Inborn genetic diseases.

What condition is associated with TRIM63 p.Ile322Thr (c.965T>C)?

TRIM63 p.Ile322Thr (c.965T>C) is associated with Inborn genetic diseases, hypertrophic cardiomyopathy (ClinVar).

How common is TRIM63 p.Ile322Thr (c.965T>C) in the general population?

TRIM63 p.Ile322Thr (c.965T>C) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about TRIM63 p.Ile322Thr (c.965T>C)?

AlphaMissense predicts likely benign (score 0.3391) — an in-silico prediction, not a clinical call.

TRIM63 p.Ile322Thr

c.965T>C · rs368532655 · VCV2514548

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3391 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3391	likely benign
REVEL	0.37	indeterminate
SaProt	LLR -9.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	24.9	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 0.00801% African / African-American · 6/74,922 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.00273% 44/1,614,040 alleles · very rare exomes 38/1,461,852 · genomes 6/152,188 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,487
European (non-Finnish)	0.00314%	31,892
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Ile322Thr
Coding: c.965T>C
MANE Select: NM_032588
dbSNP: rs368532655
Type: single nucleotide variant
Location: chr1:26057217 (GRCh38)
Gene constraint: LOEUF 1.329 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.88 · 3 PDB
Residue 322: 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)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypertrophic cardiomyopathy

Similar variants

TRIM63 p.Arg112Gln Uncertain significance ★★ ⚠ same condition
TRIM63 p.Arg183His Uncertain significance ★★ ⚠ same condition
TRIM63 p.Arg230Trp Uncertain significance ★★ ⚠ same condition
TRIM63 p.Arg62Gln Uncertain significance ★★ ⚠ same condition
TRIM63 p.Arg79Cys Uncertain significance ★★ ⚠ same condition
TRIM63 p.Gln190Lys Uncertain significance ★★ ⚠ same condition
TRIM63 p.Pro113Leu Uncertain significance ★★ ⚠ same condition
TRIM63 p.Pro57Arg 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/trim63-p-ile322thr (accessed [today's date]).

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