Is TRRAP p.Ile3532Phe (c.10594A>T) pathogenic?

TRRAP p.Ile3532Phe (c.10594A>T) is classified Uncertain significance in TRRAP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-27). AlphaMissense: likely pathogenic (0.7793); Very rare (popmax 0.000169%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TRRAP p.Ile3532Phe (c.10594A>T)?

TRRAP p.Ile3532Phe (c.10594A>T) is associated with Inborn genetic diseases (ClinVar).

How common is TRRAP p.Ile3532Phe (c.10594A>T) in the general population?

TRRAP p.Ile3532Phe (c.10594A>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about TRRAP p.Ile3532Phe (c.10594A>T)?

AlphaMissense predicts likely pathogenic (score 0.7793) — an in-silico prediction, not a clinical call.

TRRAP p.Ile3532Phe

c.10594A>T · rs974640813 · VCV1974963

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7793 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7793	likely pathogenic
REVEL	0.793	moderately pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 4,047 bp · p 4.4e-05 · regional, not allelic
Overall
CADD	24.8	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I3518F vs ClinVar I3532F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,046 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,772 alleles · very rare

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: TRRAP
Protein: p.Ile3532Phe
Coding: c.10594A>T
MANE Select: NM_001375524
dbSNP: rs974640813
Type: single nucleotide variant
Location: chr7:99005189 (GRCh38)
Gene constraint: LOEUF 0.115 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 3532: the pi3k/pi4k catalytic domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRRAP c.8247+5G>T Uncertain significance ★★ same condition
TRRAP p.Ala1055Thr Uncertain significance ★★ same condition
TRRAP p.Ala1880Val Uncertain significance ★★ ⚠ same condition
TRRAP p.Ala1895Val Uncertain significance ★★ same condition
TRRAP p.Ala1995Thr Uncertain significance ★★ same condition
TRRAP p.Ala2656Thr Uncertain significance ★★ ⚠ same condition
TRRAP p.Ala322Ser Uncertain significance ★★ ⚠ same condition
TRRAP p.Ala3616Thr Uncertain significance ★★ ⚠ same condition

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/trrap-p-ile3532phe (accessed [today's date]).

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