Is TRRAP p.Arg447Gln (c.1340G>A) pathogenic?

TRRAP p.Arg447Gln (c.1340G>A) is classified Uncertain significance in TRRAP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-27). AlphaMissense: ambiguous (0.3927); Very rare (popmax 0.00223%, eas); Associated with TRRAP-related neurodevelopmental disorder.

What condition is associated with TRRAP p.Arg447Gln (c.1340G>A)?

TRRAP p.Arg447Gln (c.1340G>A) is associated with TRRAP-related neurodevelopmental disorder (ClinVar).

How common is TRRAP p.Arg447Gln (c.1340G>A) in the general population?

TRRAP p.Arg447Gln (c.1340G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about TRRAP p.Arg447Gln (c.1340G>A)?

AlphaMissense predicts ambiguous (score 0.3927) — an in-silico prediction, not a clinical call.

TRRAP p.Arg447Gln

c.1340G>A · rs1475196953 · VCV989345

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3927 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

TRRAP-related neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.3927	ambiguous
REVEL	0.328	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 29 kb · p 1.3e-20 · regional, not allelic
Overall
CADD	27.2	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

Grpmax group 0.00223% East Asian · 1/44,840 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000744% 12/1,612,992 alleles · very rare exomes 9/1,460,902 · genomes 3/152,090 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,840
Remaining individualsnot grpmax-eligible	0.0016%	62,454
Finnishnot grpmax-eligible	0.00156%	63,986
South Asian	0.0011%	90,878
European (non-Finnish)	0.000678%	147,436

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.Arg447Gln
Coding: c.1340G>A
MANE Select: NM_001375524
dbSNP: rs1475196953
Type: single nucleotide variant
Location: chr7:98908952 (GRCh38)
Gene constraint: LOEUF 0.115 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 447: an α-helix

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

Disease context

TRRAP-related neurodevelopmental disorder

Similar variants

TRRAP p.Arg447Trp Uncertain significance ★★ ⚠ same residue
TRRAP p.Arg1562Gln Uncertain significance ★★ same condition
TRRAP p.Ile3068Val Uncertain significance ★★ ⚠ same condition
TRRAP p.Met3545Ile Uncertain significance ★★ same condition
TRRAP p.Pro3761Leu Uncertain significance ★★ same condition
TRRAP p.Thr2139Ser Uncertain significance ★★ same condition
TRRAP p.Tyr2171Cys Uncertain significance ★★ ⚠ same condition
TRRAP p.Val2020Ile 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-arg447gln (accessed [today's date]).

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