Is TRRAP p.Ile258Val (c.772A>G) pathogenic?

TRRAP p.Ile258Val (c.772A>G) is classified Uncertain significance in TRRAP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-12-01). AlphaMissense: likely benign (0.2317); Very rare (popmax 0.00223%, eas).

How common is TRRAP p.Ile258Val (c.772A>G) in the general population?

TRRAP p.Ile258Val (c.772A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about TRRAP p.Ile258Val (c.772A>G)?

AlphaMissense predicts likely benign (score 0.2317) — an in-silico prediction, not a clinical call.

TRRAP p.Ile258Val

c.772A>G · rs1584283772 · VCV1311844

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2317 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.2317	likely benign
REVEL	0.196	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 29 kb · p 1.3e-20 · regional, not allelic
Overall
CADD	23.3	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,884 alleles

Overall 0.000124% 2/1,614,174 alleles · very rare exomes 2/1,461,890 · genomes 0/152,284 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,884
European (non-Finnish)	8.47e-05%	1,180,025

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.Ile258Val
Coding: c.772A>G
MANE Select: NM_001375524
dbSNP: rs1584283772
Type: single nucleotide variant
Location: chr7:98899739 (GRCh38)
Gene constraint: LOEUF 0.115 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 258: an α-helix

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

Similar variants

TRRAP p.Arg1035Gln Pathogenic/Likely pathogenic ★★ same type
TRRAP p.Glu1104Gly Pathogenic/Likely pathogenic ★★ same type
TRRAP p.Glu1106Lys Likely pathogenic ★★ same type
TRRAP p.Met3318Val Pathogenic/Likely pathogenic ★★ same type
TRRAP p.Val1030Ile Likely pathogenic ★★ same type
TRRAP c.2622+3A>G Uncertain significance ★★ same type
TRRAP c.7176+4A>G Uncertain significance ★★ same type
TRRAP c.8247+5G>T Uncertain significance ★★ same type

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-ile258val (accessed [today's date]).

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