Is TRAP1 p.Ala649Val (c.1946C>T) pathogenic?

TRAP1 p.Ala649Val (c.1946C>T) is classified Uncertain significance in TRAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-04). AlphaMissense: likely benign (0.0721); Rare (popmax 0.181%, mid).

How common is TRAP1 p.Ala649Val (c.1946C>T) in the general population?

TRAP1 p.Ala649Val (c.1946C>T) is rare (popmax 0.181%, mid) (gnomAD).

What do computational predictors say about TRAP1 p.Ala649Val (c.1946C>T)?

AlphaMissense predicts likely benign (score 0.0721) — an in-silico prediction, not a clinical call.

TRAP1 p.Ala649Val

c.1946C>T · rs147353660 · VCV2713169

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0721 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.181%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0721	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -6.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.7	GERP -3.4
Regional constraint	o/e 1.33	unconstrained · MANE · 59 kb · p 5.2e-24 · regional, not allelic
Overall
CADD	4.902	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 0.181% Middle Eastern · 11/6,062 alleles

Filtering AF 0.116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.114%

Overall 0.102% 1,653/1,614,008 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.181%	551
Remaining individualsnot grpmax-eligible	0.13%	772
European (non-Finnish)	0.122%	822
South Asian	0.0747%	1,339
East Asian	0.0334%	2,992
Admixed American	0.0283%	3,530
Finnishnot grpmax-eligible	0.025%	3,996
African / African-American	0.012%	8,338

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.Ala649Val
Coding: c.1946C>T
MANE Select: NM_005223 · reported on NM_016292
dbSNP: rs147353660
Type: single nucleotide variant
Location: chr16:3658860 (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-ala649val (accessed [today's date]).

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