Is TRAP1 p.Arg540Cys (c.1618C>T) pathogenic?

TRAP1 p.Arg540Cys (c.1618C>T) is classified Uncertain significance in TRAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-05). AlphaMissense: likely benign (0.2706); Very rare (popmax 0.00333%, amr).

How common is TRAP1 p.Arg540Cys (c.1618C>T) in the general population?

TRAP1 p.Arg540Cys (c.1618C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about TRAP1 p.Arg540Cys (c.1618C>T)?

AlphaMissense predicts likely benign (score 0.2706) — an in-silico prediction, not a clinical call.

TRAP1 p.Arg540Cys

c.1618C>T · rs769933824 · VCV1521576

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2706 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2706	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -12.32	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.33	unconstrained · MANE · 59 kb · p 5.2e-24 · regional, not allelic
Overall
CADD	26.2	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 0.00333% Admixed American · 2/60,002 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000991% 16/1,613,990 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,001
Remaining individualsnot grpmax-eligible	0.0032%	31,241
South Asian	0.0011%	91,084
European (non-Finnish)	0.000932%	107,275

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.Arg540Cys
Coding: c.1618C>T
MANE Select: NM_005223 · reported on NM_016292
dbSNP: rs769933824
Type: single nucleotide variant
Location: chr16:3663514 (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-arg540cys (accessed [today's date]).

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