Is TRAP1 p.Pro476Leu (c.1427C>T) pathogenic?

TRAP1 p.Pro476Leu (c.1427C>T) is classified Uncertain significance in TRAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-21). AlphaMissense: likely benign (0.1263); Ultra-rare (popmax 0.0173%, afr).

How common is TRAP1 p.Pro476Leu (c.1427C>T) in the general population?

TRAP1 p.Pro476Leu (c.1427C>T) is ultra-rare (popmax 0.0173%, afr) (gnomAD).

What do computational predictors say about TRAP1 p.Pro476Leu (c.1427C>T)?

AlphaMissense predicts likely benign (score 0.1263) — an in-silico prediction, not a clinical call.

TRAP1 p.Pro476Leu

c.1427C>T · rs200185978 · VCV1365798

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1263 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

⚠ 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	0.1263	likely benign
REVEL	0.382	indeterminate
SaProt	LLR -12.24	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.33	unconstrained · MANE · 59 kb · p 5.2e-24 · regional, not allelic
Overall
CADD	23.4	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 0.0173% African / African-American · 13/75,026 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00812%

Overall 0.00143% 23/1,612,170 alleles · ultra-rare exomes 8/1,459,870 · genomes 15/152,300 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0173%	5,771
Admixed American	0.0067%	14,931
Remaining individualsnot grpmax-eligible	0.00481%	20,792
European (non-Finnish)	0.000254%	393,108

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.Pro476Leu
Coding: c.1427C>T
MANE Select: NM_016292
dbSNP: rs200185978
Type: single nucleotide variant
Location: chr16:3664416 (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-pro476leu (accessed [today's date]).

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