Is TRAP1 p.Arg326Cys (c.976C>T) pathogenic?

TRAP1 p.Arg326Cys (c.976C>T) is classified Uncertain significance in TRAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.1313); Ultra-rare (popmax 0.0527%, sas).

How common is TRAP1 p.Arg326Cys (c.976C>T) in the general population?

TRAP1 p.Arg326Cys (c.976C>T) is ultra-rare (popmax 0.0527%, sas) (gnomAD).

What do computational predictors say about TRAP1 p.Arg326Cys (c.976C>T)?

AlphaMissense predicts likely benign (score 0.1313) — an in-silico prediction, not a clinical call.

TRAP1 p.Arg326Cys

c.976C>T · VCV4190007

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1313 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0527%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1313	likely benign
REVEL	0.505	indeterminate
SaProt	LLR -7.52	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.33	unconstrained · MANE · 59 kb · p 5.2e-24 · regional, not allelic
Overall
CADD	31.0	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 0.0527% South Asian · 48/91,084 alleles

Filtering AF 0.0408% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0366%

Overall 0.00576% 93/1,614,120 alleles · ultra-rare exomes 81/1,461,798 · genomes 12/152,322 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0527%	1,898
Remaining individualsnot grpmax-eligible	0.0096%	10,418
Admixed American	0.005%	20,008
East Asian	0.00446%	22,442
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
European (non-Finnish)	0.00263%	38,066
Finnishnot grpmax-eligible	0.00156%	63,956
African / African-American	0.00133%	75,048

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.Arg326Cys
Coding: c.976C>T
MANE Select: NM_016292
Type: single nucleotide variant
Location: chr16:3674407 (GRCh38)
Gene constraint: LOEUF 1.343 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.28 · 24 PDB
Residue 326: a β-strand

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

Similar variants

TRAP1 p.Arg326His Uncertain significance ★ ⚠ same residue
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

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-arg326cys (accessed [today's date]).

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