Is TRAP1 p.Ser549Phe (c.1646C>T) pathogenic?

TRAP1 p.Ser549Phe (c.1646C>T) is classified Uncertain significance in TRAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). AlphaMissense: likely pathogenic (0.9866); Absent from gnomAD v4.1.

How common is TRAP1 p.Ser549Phe (c.1646C>T) in the general population?

TRAP1 p.Ser549Phe (c.1646C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TRAP1 p.Ser549Phe (c.1646C>T)?

AlphaMissense predicts likely pathogenic (score 0.9866) — an in-silico prediction, not a clinical call.

TRAP1 p.Ser549Phe

c.1646C>T · VCV3972976

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9866 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9866	likely pathogenic · top 5% in TRAP1
REVEL	0.553	indeterminate
SaProt	LLR -13.64	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.37	gain · loss 0.00 · not in the SpliceAI release · independent
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 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TRAP1
Protein: p.Ser549Phe
Coding: c.1646C>T
MANE Select: NM_016292
Type: single nucleotide variant
Location: chr16:3663486 (GRCh38)
Gene constraint: LOEUF 1.343 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.28 · 24 PDB
Residue 549: a β-strand

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

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-ser549phe (accessed [today's date]).

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