Is TRRAP p.Val453Phe (c.1357G>T) pathogenic?

TRRAP p.Val453Phe (c.1357G>T) is classified Uncertain significance in TRRAP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-05). AlphaMissense: likely pathogenic (0.9934); Absent from gnomAD v4.1; Associated with developmental delay with or without dysmorphic facies and autism.

What condition is associated with TRRAP p.Val453Phe (c.1357G>T)?

TRRAP p.Val453Phe (c.1357G>T) is associated with developmental delay with or without dysmorphic facies and autism (ClinVar).

How common is TRRAP p.Val453Phe (c.1357G>T) in the general population?

TRRAP p.Val453Phe (c.1357G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TRRAP p.Val453Phe (c.1357G>T)?

AlphaMissense predicts likely pathogenic (score 0.9934) — an in-silico prediction, not a clinical call.

TRRAP p.Val453Phe

c.1357G>T · VCV3572881

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9934 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

developmental delay with or without dysmorphic facies and autism

Computational evidence

Protein change
AlphaMissense	0.9934	likely pathogenic
REVEL	0.534	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.23	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 29 kb · p 1.3e-20 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

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: TRRAP
Protein: p.Val453Phe
Coding: c.1357G>T
MANE Select: NM_001375524
Type: single nucleotide variant
Location: chr7:98910062 (GRCh38)
Gene constraint: LOEUF 0.115 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 453: an α-helix

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

Disease context

developmental delay with or without dysmorphic facies and autism — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRRAP p.Val453Ile Uncertain significance ★ same residue
TRRAP p.Arg1035Gln Pathogenic/Likely pathogenic ★★ same condition
TRRAP p.Glu1104Gly Pathogenic/Likely pathogenic ★★ same condition
TRRAP p.Met3318Val Pathogenic/Likely pathogenic ★★ same condition
TRRAP p.Ala1995Thr Uncertain significance ★★ same condition
TRRAP p.Ala3669Val Uncertain significance ★★ ⚠ same condition
TRRAP p.Ala3764Val Uncertain significance ★★ same condition
TRRAP p.Ala953Thr 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-val453phe (accessed [today's date]).

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