Is TRAP1 p.Arg593His (c.1778G>A) pathogenic?

TRAP1 p.Arg593His (c.1778G>A) is classified Uncertain significance in TRAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-12-24). AlphaMissense: likely benign (0.1084); Ultra-rare (popmax 0.0617%, amr).

How common is TRAP1 p.Arg593His (c.1778G>A) in the general population?

TRAP1 p.Arg593His (c.1778G>A) is ultra-rare (popmax 0.0617%, amr) (gnomAD).

What do computational predictors say about TRAP1 p.Arg593His (c.1778G>A)?

AlphaMissense predicts likely benign (score 0.1084) — an in-silico prediction, not a clinical call.

TRAP1 p.Arg593His

c.1778G>A · rs145850823 · VCV1960132

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1084 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0617%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1084	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -8.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 3.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.33	unconstrained · MANE · 59 kb · p 5.2e-24 · regional, not allelic
Overall
CADD	22.8	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 0.0617% Admixed American · 37/60,006 alleles

Filtering AF 0.0459% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0405%

Overall 0.00948% 153/1,613,464 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0617%	1,622
European (non-Finnish)	0.00898%	11,132
Remaining individualsnot grpmax-eligible	0.008%	12,496
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
African / African-American	0.00267%	37,467
South Asian	0.0022%	45,546

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: TRAP1
Protein: p.Arg593His
Coding: c.1778G>A
MANE Select: NM_005223 · reported on NM_016292
dbSNP: rs145850823
Type: single nucleotide variant
Location: chr16:3662898 (GRCh38)

Full TRAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/trap1-p-arg593his (accessed [today's date]).

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