Is TRRAP p.Pro1220Arg (c.3659C>G) pathogenic?

TRRAP p.Pro1220Arg (c.3659C>G) is classified Uncertain significance in TRRAP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-12). AlphaMissense: likely benign (0.2569); Absent from gnomAD v4.1; Associated with developmental delay with or without dysmorphic facies and autism.

What condition is associated with TRRAP p.Pro1220Arg (c.3659C>G)?

TRRAP p.Pro1220Arg (c.3659C>G) is associated with developmental delay with or without dysmorphic facies and autism (ClinVar).

How common is TRRAP p.Pro1220Arg (c.3659C>G) in the general population?

TRRAP p.Pro1220Arg (c.3659C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TRRAP p.Pro1220Arg (c.3659C>G)?

AlphaMissense predicts likely benign (score 0.2569) — an in-silico prediction, not a clinical call.

TRRAP p.Pro1220Arg

c.3659C>G · VCV3901850

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2569 · 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	0.2569	likely benign
REVEL	0.428	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 3,095 bp · p 2.8e-06 · regional, not allelic
Overall
CADD	23.5	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.Pro1220Arg
Coding: c.3659C>G
MANE Select: NM_001375524
Type: single nucleotide variant
Location: chr7:98931472 (GRCh38)
Gene constraint: LOEUF 0.115 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 1220: 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.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
TRRAP p.Arg171His 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-pro1220arg (accessed [today's date]).

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