Is TRAP1 p.Asp158His (c.472G>C) pathogenic?

TRAP1 p.Asp158His (c.472G>C) is classified Uncertain significance in TRAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-27). AlphaMissense: likely pathogenic (0.9976); Ultra-rare (popmax 0.0317%, amr); Associated with VACTERL/vater association.

What condition is associated with TRAP1 p.Asp158His (c.472G>C)?

TRAP1 p.Asp158His (c.472G>C) is associated with VACTERL/vater association (ClinVar).

How common is TRAP1 p.Asp158His (c.472G>C) in the general population?

TRAP1 p.Asp158His (c.472G>C) is ultra-rare (popmax 0.0317%, amr) (gnomAD).

What do computational predictors say about TRAP1 p.Asp158His (c.472G>C)?

AlphaMissense predicts likely pathogenic (score 0.9976) — an in-silico prediction, not a clinical call.

TRAP1 p.Asp158His

c.472G>C · rs769418685 · VCV2442134

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9976 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

VACTERL/vater association

Computational evidence

Protein change
AlphaMissense	0.9976	likely pathogenic · top 1% in TRAP1
REVEL	0.985	strongly pathogenic-leaning
SaProt	LLR -14.57	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 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.33	unconstrained · MANE · 59 kb · p 5.2e-24 · regional, not allelic
Overall
CADD	34.0	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 0.0317% Admixed American · 19/60,006 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00136% 22/1,613,948 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0317%	3,158
Middle Eastern	0.0164%	6,084
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
European (non-Finnish)	8.47e-05%	1,180,018

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.Asp158His
Coding: c.472G>C
MANE Select: NM_016292
dbSNP: rs769418685
Type: single nucleotide variant
Location: chr16:3679790 (GRCh38)
Gene constraint: LOEUF 1.343 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.28 · 24 PDB
Residue 158: a binding site; a β-strand

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

Disease context

VACTERL/vater association — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRAP1 p.Ala319Val Uncertain significance ★★ ⚠ same type
TRAP1 p.Ala409Thr Uncertain significance ★★ ⚠ same type
TRAP1 p.Ala50Ser Uncertain significance ★★ ⚠ same type
TRAP1 p.Ala64Thr Uncertain significance ★★ ⚠ same type
TRAP1 p.Ala659Thr Uncertain significance ★★ ⚠ same type
TRAP1 p.Ala7Val Uncertain significance ★★ ⚠ same type
TRAP1 p.Arg271Pro Uncertain significance ★★ ⚠ same type
TRAP1 p.Arg340His Uncertain significance ★★ ⚠ same type

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-asp158his (accessed [today's date]).

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