Is TRAP1 p.Arg540His (c.1619G>A) pathogenic?

TRAP1 p.Arg540His (c.1619G>A) is classified Uncertain significance in TRAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-01-10). AlphaMissense: likely benign (0.134); Very rare (popmax 0.00988%, sas).

How common is TRAP1 p.Arg540His (c.1619G>A) in the general population?

TRAP1 p.Arg540His (c.1619G>A) is very rare (popmax 0.00988%, sas) (gnomAD).

What do computational predictors say about TRAP1 p.Arg540His (c.1619G>A)?

AlphaMissense predicts likely benign (score 0.134) — an in-silico prediction, not a clinical call.

TRAP1 p.Arg540His

c.1619G>A · rs141361125 · VCV1943105

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.134 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00988%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.134	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -9.19	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 0.76, 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 0.00988% South Asian · 9/91,082 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00375%

Overall 0.00161% 26/1,614,002 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00988%	10,120
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	0.00136%	73,753

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.Arg540His
Coding: c.1619G>A
MANE Select: NM_005223 · reported on NM_016292
dbSNP: rs141361125
Type: single nucleotide variant
Location: chr16:3663513 (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-arg540his (accessed [today's date]).

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