Is TRIM63 p.Ala218Val (c.653C>T) pathogenic?

TRIM63 p.Ala218Val (c.653C>T) is classified Conflicting classifications of pathogenicity in TRIM63 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-20). AlphaMissense: likely benign (0.1143); Rare (popmax 0.22%, afr).

How common is TRIM63 p.Ala218Val (c.653C>T) in the general population?

TRIM63 p.Ala218Val (c.653C>T) is rare (popmax 0.22%, afr) (gnomAD).

What do computational predictors say about TRIM63 p.Ala218Val (c.653C>T)?

AlphaMissense predicts likely benign (score 0.1143) — an in-silico prediction, not a clinical call.

TRIM63 p.Ala218Val

c.653C>T · rs141049472 · VCV3629610

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1143 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.22%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1143	likely benign
REVEL	0.195	benign-leaning
SaProt	LLR -8.36	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.7	GERP 1.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 16 kb · p 0.51 · regional, not allelic
Overall
CADD	23.9	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 0.22% African / African-American · 165/75,036 alleles

Filtering AF 0.193% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.182%

Overall 0.0113% 183/1,614,162 alleles · rare exomes 90/1,461,884 · genomes 93/152,278 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.22%	455
Remaining individualsnot grpmax-eligible	0.0144%	6,945
Admixed American	0.0117%	8,573
European (non-Finnish)	0.000169%	590,016

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.Ala218Val
Coding: c.653C>T
MANE Select: NM_032588
dbSNP: rs141049472
Type: single nucleotide variant
Location: chr1:26058568 (GRCh38)
Gene constraint: LOEUF 1.329 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.88 · 3 PDB
Residue 218: the 'interaction with ttn' region; an α-helix

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

Similar variants

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
TRIM63 p.Arg62Gln Uncertain significance ★★ ⚠ same type
TRIM63 p.Arg62Trp Uncertain significance ★★ ⚠ same type
TRIM63 p.Arg74His 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-ala218val (accessed [today's date]).

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