Is TRAP1 p.Pro686Arg (c.2057C>G) pathogenic?

TRAP1 p.Pro686Arg (c.2057C>G) is classified Uncertain significance in TRAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-18). AlphaMissense: likely pathogenic (0.8111); Ultra-rare (popmax 0.0657%, mid); Associated with TRAP1-related disorder.

What condition is associated with TRAP1 p.Pro686Arg (c.2057C>G)?

TRAP1 p.Pro686Arg (c.2057C>G) is associated with TRAP1-related disorder (ClinVar).

How common is TRAP1 p.Pro686Arg (c.2057C>G) in the general population?

TRAP1 p.Pro686Arg (c.2057C>G) is ultra-rare (popmax 0.0657%, mid) (gnomAD).

What do computational predictors say about TRAP1 p.Pro686Arg (c.2057C>G)?

AlphaMissense predicts likely pathogenic (score 0.8111) — an in-silico prediction, not a clinical call.

TRAP1 p.Pro686Arg

c.2057C>G · rs995881750 · VCV2636594

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8111 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0657%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

TRAP1-related disorder

Computational evidence

Protein change
AlphaMissense	0.8111	likely pathogenic
REVEL	0.454	indeterminate
SaProt	LLR -14.36	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.4	GERP 0.73, phastCons 1
Regional constraint	o/e 1.33	unconstrained · MANE · 59 kb · p 5.2e-24 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0657% Middle Eastern · 4/6,084 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.000558% 9/1,613,976 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0657%	1,521
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)	0.000254%	393,338

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.Pro686Arg
Coding: c.2057C>G
MANE Select: NM_005223 · reported on NM_016292
dbSNP: rs995881750
Type: single nucleotide variant
Location: chr16:3658187 (GRCh38)

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

Disease context

TRAP1-related disorder

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-pro686arg (accessed [today's date]).

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