Is TRIM63 p.Arg74Cys (c.220C>T) pathogenic?

TRIM63 p.Arg74Cys (c.220C>T) is classified Uncertain significance in TRIM63 (ClinVar, Single submitter, 1 submitter). AlphaMissense: ambiguous (0.5302); Ultra-rare (popmax 0.0132%, sas); Associated with hypertrophic cardiomyopathy.

What condition is associated with TRIM63 p.Arg74Cys (c.220C>T)?

TRIM63 p.Arg74Cys (c.220C>T) is associated with hypertrophic cardiomyopathy (ClinVar).

How common is TRIM63 p.Arg74Cys (c.220C>T) in the general population?

TRIM63 p.Arg74Cys (c.220C>T) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

What do computational predictors say about TRIM63 p.Arg74Cys (c.220C>T)?

AlphaMissense predicts ambiguous (score 0.5302) — an in-silico prediction, not a clinical call.

TRIM63 p.Arg74Cys

c.220C>T · rs750066412 · VCV978745

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5302 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hypertrophic cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.5302	ambiguous
REVEL	0.879	moderately pathogenic-leaning
SaProt	LLR -13.26	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 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 16 kb · p 0.51 · regional, not allelic
Overall
CADD	34.0	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 0.0132% South Asian · 12/91,014 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.00192% 31/1,613,084 alleles · ultra-rare exomes 28/1,460,904 · genomes 3/152,180 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,584
African / African-American	0.00401%	24,967
East Asian	0.00223%	44,878
Admixed American	0.00167%	59,936
Remaining individualsnot grpmax-eligible	0.0016%	62,440
European (non-Finnish)	0.0011%	90,731

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.Arg74Cys
Coding: c.220C>T
MANE Select: NM_032588
dbSNP: rs750066412
Type: single nucleotide variant
Location: chr1:26066380 (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

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

Similar variants

TRIM63 p.Arg74His Uncertain significance ★★ ⚠ same residue
TRIM63 p.Arg112Gln Uncertain significance ★★ ⚠ same condition
TRIM63 c.1051+1G>A 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-arg74cys (accessed [today's date]).

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