Is TRAP1 p.Arg540Pro (c.1619G>C) pathogenic?

TRAP1 p.Arg540Pro (c.1619G>C) is classified Uncertain significance in TRAP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-19). AlphaMissense: likely pathogenic (0.6955); Ultra-rare (popmax 0.0329%, mid).

How common is TRAP1 p.Arg540Pro (c.1619G>C) in the general population?

TRAP1 p.Arg540Pro (c.1619G>C) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about TRAP1 p.Arg540Pro (c.1619G>C)?

AlphaMissense predicts likely pathogenic (score 0.6955) — an in-silico prediction, not a clinical call.

TRAP1 p.Arg540Pro

c.1619G>C · rs141361125 · VCV1948803

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6955 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.6955	likely pathogenic
REVEL	0.202	benign-leaning
SaProt	LLR -13.25	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
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	22.3	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.0018% 29/1,614,002 alleles · ultra-rare exomes 25/1,461,864 · genomes 4/152,138 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0574%	1,741
Middle Easterngrpmax	0.0329%	3,042
Remaining individualsnot grpmax-eligible	0.0064%	15,621
South Asian	0.0011%	91,082
European (non-Finnish)	0.000424%	236,009

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg540Pro
Coding: c.1619G>C
MANE Select: 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-arg540pro (accessed [today's date]).

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