Is ARAP2 p.Val1415Met (c.4243G>A) pathogenic?

ARAP2 p.Val1415Met (c.4243G>A) is classified Uncertain significance in ARAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely pathogenic (0.6393); Ultra-rare (popmax 0.0199%, nfe).

How common is ARAP2 p.Val1415Met (c.4243G>A) in the general population?

ARAP2 p.Val1415Met (c.4243G>A) is ultra-rare (popmax 0.0199%, nfe) (gnomAD).

What do computational predictors say about ARAP2 p.Val1415Met (c.4243G>A)?

AlphaMissense predicts likely pathogenic (score 0.6393) — an in-silico prediction, not a clinical call.

ARAP2 p.Val1415Met

c.4243G>A · rs370690698 · VCV2459746

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6393 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0199%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6393	likely pathogenic
REVEL	0.169	moderately benign-leaning
SaProt	LLR -11.16	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 162 kb · p 0.0019 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0199% European (non-Finnish) · 234/1,178,118 alleles

Filtering AF 0.0178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0169%

Overall 0.0148% 239/1,610,678 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0199%	5,035
Remaining individualsnot grpmax-eligible	0.00321%	31,153
African / African-American	0.00268%	37,363
South Asian	0.0011%	90,788

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: ARAP2
Protein: p.Val1415Met
Coding: c.4243G>A
MANE Select: NM_015230
dbSNP: rs370690698
Type: single nucleotide variant
Location: chr4:36107607 (GRCh38)
Gene constraint: LOEUF 0.884 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.42 · 2 PDB
Residue 1415: the ras-associating domain

Full ARAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARAP2 p.Ala1241Thr Uncertain significance ★ ⚠ same type
ARAP2 p.Ala1261Thr Uncertain significance ★ ⚠ same type
ARAP2 p.Ala1261Val Uncertain significance ★ ⚠ same type
ARAP2 p.Ala1353Glu Uncertain significance ★ ⚠ same type
ARAP2 p.Ala1375Pro Uncertain significance ★ ⚠ same type
ARAP2 p.Ala1421Ser Uncertain significance ★ ⚠ same type
ARAP2 p.Ala1421Thr Uncertain significance ★ ⚠ same type
ARAP2 p.Ala1508Thr 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/arap2-p-val1415met (accessed [today's date]).

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