Is ARAP2 p.Phe894Leu (c.2682C>A) pathogenic?

ARAP2 p.Phe894Leu (c.2682C>A) is classified Uncertain significance in ARAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-27). AlphaMissense: likely pathogenic (0.9617); Ultra-rare (popmax 0.0973%, sas).

How common is ARAP2 p.Phe894Leu (c.2682C>A) in the general population?

ARAP2 p.Phe894Leu (c.2682C>A) is ultra-rare (popmax 0.0973%, sas) (gnomAD).

What do computational predictors say about ARAP2 p.Phe894Leu (c.2682C>A)?

AlphaMissense predicts likely pathogenic (score 0.9617) — an in-silico prediction, not a clinical call.

ARAP2 p.Phe894Leu

c.2682C>A · rs535975360 · VCV3128233

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9617 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0973%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9617	likely pathogenic · top 9% in ARAP2
REVEL	0.624	indeterminate
SaProt	LLR -3.18	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -1.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 162 kb · p 0.0019 · regional, not allelic
Overall
CADD	20.6	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 0.0973% South Asian · 88/90,472 alleles

Filtering AF 0.0808% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0747%

Overall 0.00577% 93/1,612,360 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0973%	1,028
Remaining individualsnot grpmax-eligible	0.00641%	15,613
East Asian	0.00223%	44,754

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.Phe894Leu
Coding: c.2682C>A
MANE Select: NM_015230
dbSNP: rs535975360
Type: single nucleotide variant
Location: chr4:36158800 (GRCh38)
Gene constraint: LOEUF 0.884 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.42 · 2 PDB
Residue 894: the ph 3 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-phe894leu (accessed [today's date]).

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