Is TRAP1 p.Ser226Arg (c.678C>G) pathogenic?

TRAP1 p.Ser226Arg (c.678C>G) is classified Uncertain significance in TRAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-18). AlphaMissense: ambiguous (0.4836); Very rare (popmax 0.00398%, nfe).

How common is TRAP1 p.Ser226Arg (c.678C>G) in the general population?

TRAP1 p.Ser226Arg (c.678C>G) is very rare (popmax 0.00398%, nfe) (gnomAD).

What do computational predictors say about TRAP1 p.Ser226Arg (c.678C>G)?

AlphaMissense predicts ambiguous (score 0.4836) — an in-silico prediction, not a clinical call.

TRAP1 p.Ser226Arg

c.678C>G · VCV3328513

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4836 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00398%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4836	ambiguous
REVEL	0.439	indeterminate
SaProt	LLR -12.21	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -0.19, phastCons 1
Regional constraint	o/e 1.33	unconstrained · MANE · 59 kb · p 5.2e-24 · regional, not allelic
Overall
CADD	19.45	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 0.00398% European (non-Finnish) · 47/1,180,042 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.0031% 50/1,614,060 alleles · very rare exomes 48/1,461,856 · genomes 2/152,204 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00398%	25,107
Remaining individualsnot grpmax-eligible	0.0032%	31,242
Admixed American	0.00167%	60,014

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.Ser226Arg
Coding: c.678C>G
MANE Select: NM_016292
Type: single nucleotide variant
Location: chr16:3677524 (GRCh38)
Gene constraint: LOEUF 1.343 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.28 · 24 PDB

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

Similar variants

TRAP1 p.Ser226Ile 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-ser226arg (accessed [today's date]).

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