Is TRIM63 p.Arg74His (c.221G>A) pathogenic?

TRIM63 p.Arg74His (c.221G>A) is classified Uncertain significance in TRIM63 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-08-20). AlphaMissense: ambiguous (0.358); Ultra-rare (popmax 0.0329%, mid); Associated with familial hypertrophic cardiomyopathy.

What condition is associated with TRIM63 p.Arg74His (c.221G>A)?

TRIM63 p.Arg74His (c.221G>A) is associated with familial hypertrophic cardiomyopathy (ClinVar).

How common is TRIM63 p.Arg74His (c.221G>A) in the general population?

TRIM63 p.Arg74His (c.221G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about TRIM63 p.Arg74His (c.221G>A)?

AlphaMissense predicts ambiguous (score 0.358) — an in-silico prediction, not a clinical call.

TRIM63 p.Arg74His

c.221G>A · rs142710853 · VCV2526644

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.358 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

familial hypertrophic cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.358	ambiguous
REVEL	0.848	moderately pathogenic-leaning
SaProt	LLR -10.87	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 16 kb · p 0.51 · regional, not allelic
Overall
CADD	30.0	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 0.0329% Middle Eastern · 2/6,078 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0116%

Overall 0.0131% 211/1,612,802 alleles · ultra-rare exomes 199/1,460,634 · genomes 12/152,168 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,039
Finnishnot grpmax-eligible	0.0204%	4,910
South Asian	0.0198%	5,055
European (non-Finnish)	0.014%	7,148
East Asian	0.00891%	11,218
African / African-American	0.00668%	14,980
Remaining individualsnot grpmax-eligible	0.00641%	15,610

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.Arg74His
Coding: c.221G>A
MANE Select: NM_032588
dbSNP: rs142710853
Type: single nucleotide variant
Location: chr1:26066379 (GRCh38)
Gene constraint: LOEUF 1.329 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.88 · 3 PDB
Residue 74: the 'interaction with ttn' region

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

Disease context

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

Similar variants

TRIM63 p.Arg74Cys Uncertain significance ★ ⚠ same residue
TRIM63 p.Gln247Ter Conflicting classifications of pathogenicity ★ same condition
TRIM63 p.Val89Met Uncertain significance ★ ⚠ same condition
TRIM63 p.Ala244Val Uncertain significance ★★ ⚠ same type
TRIM63 p.Ala289Val Uncertain significance ★★ ⚠ same type
TRIM63 p.Arg112Gln Uncertain significance ★★ ⚠ same type
TRIM63 p.Arg183His Uncertain significance ★★ ⚠ same type
TRIM63 p.Arg230Trp 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-arg74his (accessed [today's date]).

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