Is TRAP1 p.Ser592Leu (c.1775C>T) pathogenic?

TRAP1 p.Ser592Leu (c.1775C>T) is classified Uncertain significance in TRAP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-01). AlphaMissense: likely benign (0.0962); Ultra-rare (popmax 0.0615%, sas).

How common is TRAP1 p.Ser592Leu (c.1775C>T) in the general population?

TRAP1 p.Ser592Leu (c.1775C>T) is ultra-rare (popmax 0.0615%, sas) (gnomAD).

What do computational predictors say about TRAP1 p.Ser592Leu (c.1775C>T)?

AlphaMissense predicts likely benign (score 0.0962) — an in-silico prediction, not a clinical call.

TRAP1 p.Ser592Leu

c.1775C>T · rs565099748 · VCV3047096

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0962 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0615%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0962	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -7.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 8.4	GERP 0.66, phastCons 1
Regional constraint	o/e 1.33	unconstrained · MANE · 59 kb · p 5.2e-24 · regional, not allelic
Overall
CADD	19.62	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 0.0615% South Asian · 56/91,074 alleles

Filtering AF 0.0486% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.044%

Overall 0.00539% 87/1,613,436 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0615%	1,626
African / African-American	0.0107%	9,381
Admixed American	0.005%	20,003
Remaining individualsnot grpmax-eligible	0.0048%	20,835
European (non-Finnish)	0.00144%	69,411

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.Ser592Leu
Coding: c.1775C>T
MANE Select: NM_016292
dbSNP: rs565099748
Type: single nucleotide variant
Location: chr16:3662901 (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-ser592leu (accessed [today's date]).

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