Is TRAP1 p.Ala608Ser (c.1822G>T) pathogenic?

TRAP1 p.Ala608Ser (c.1822G>T) is classified Uncertain significance in TRAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-19). AlphaMissense: likely benign (0.2278); Ultra-rare (popmax 0.0988%, mid).

How common is TRAP1 p.Ala608Ser (c.1822G>T) in the general population?

TRAP1 p.Ala608Ser (c.1822G>T) is ultra-rare (popmax 0.0988%, mid) (gnomAD).

What do computational predictors say about TRAP1 p.Ala608Ser (c.1822G>T)?

AlphaMissense predicts likely benign (score 0.2278) — an in-silico prediction, not a clinical call.

TRAP1 p.Ala608Ser

c.1822G>T · rs142421032 · VCV2196490

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2278 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0988%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2278	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR -6.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.33	unconstrained · MANE · 59 kb · p 5.2e-24 · regional, not allelic
Overall
CADD	24.3	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 0.0988% Middle Eastern · 6/6,070 alleles

Filtering AF 0.043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0303%

Overall 0.0098% 158/1,612,788 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.108%	923
Middle Easterngrpmax	0.0988%	1,012
African / African-American	0.0467%	2,141
Admixed American	0.03%	3,330
Remaining individualsnot grpmax-eligible	0.0272%	3,673
European (non-Finnish)	0.00407%	24,577
Finnishnot grpmax-eligible	0.00316%	31,684

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala608Ser
Coding: c.1822G>T
MANE Select: NM_005223 · reported on NM_016292
dbSNP: rs142421032
Type: single nucleotide variant
Location: chr16:3662105 (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-ala608ser (accessed [today's date]).

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