Is TRAP1 p.Trp231Arg (c.691T>C) pathogenic?

TRAP1 p.Trp231Arg (c.691T>C) is classified Uncertain significance in TRAP1 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-02-11). AlphaMissense: likely pathogenic (0.9988); Very rare (popmax 0.00229%, nfe).

How common is TRAP1 p.Trp231Arg (c.691T>C) in the general population?

TRAP1 p.Trp231Arg (c.691T>C) is very rare (popmax 0.00229%, nfe) (gnomAD).

What do computational predictors say about TRAP1 p.Trp231Arg (c.691T>C)?

AlphaMissense predicts likely pathogenic (score 0.9988) — an in-silico prediction, not a clinical call.

TRAP1 p.Trp231Arg

c.691T>C · rs1478013745 · VCV592056

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9988 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9988	likely pathogenic · top 1% in TRAP1
REVEL	0.806	moderately pathogenic-leaning
SaProt	LLR -12.88	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.33	unconstrained · MANE · 59 kb · p 5.2e-24 · regional, not allelic
Overall
CADD	26.8	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 0.00229% European (non-Finnish) · 27/1,180,038 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00173% 28/1,614,060 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00229%	43,705
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Trp231Arg
Coding: c.691T>C
MANE Select: NM_016292
dbSNP: rs1478013745
Type: single nucleotide variant
Location: chr16:3677511 (GRCh38)
Gene constraint: LOEUF 1.343 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.28 · 24 PDB
Residue 231: a β-strand

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

Similar variants

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TRAP1 p.Ala64Thr Uncertain significance ★★ ⚠ same type
TRAP1 p.Ala659Thr Uncertain significance ★★ ⚠ same type
TRAP1 p.Ala7Val Uncertain significance ★★ ⚠ same type
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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-trp231arg (accessed [today's date]).

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