Is ARAP2 p.Leu804Ser (c.2411T>C) pathogenic?

ARAP2 p.Leu804Ser (c.2411T>C) is classified Uncertain significance in ARAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: ambiguous (0.359); Ultra-rare (popmax 0.0419%, mid).

How common is ARAP2 p.Leu804Ser (c.2411T>C) in the general population?

ARAP2 p.Leu804Ser (c.2411T>C) is ultra-rare (popmax 0.0419%, mid) (gnomAD).

What do computational predictors say about ARAP2 p.Leu804Ser (c.2411T>C)?

AlphaMissense predicts ambiguous (score 0.359) — an in-silico prediction, not a clinical call.

ARAP2 p.Leu804Ser

c.2411T>C · VCV4130026

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.359 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0419%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.359	ambiguous
REVEL	0.063	moderately benign-leaning
SaProt	LLR -4.98	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 1.4, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 162 kb · p 0.0019 · regional, not allelic
Overall
CADD	19.63	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 0.0419% Middle Eastern · 2/4,772 alleles

Filtering AF 0.00737% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00573%

Overall 0.00606% 95/1,566,782 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0419%	2,386
European (non-Finnish)	0.00748%	13,367
Remaining individualsnot grpmax-eligible	0.00662%	15,110
Ashkenazi Jewishnot grpmax-eligible	0.00349%	28,660
African / African-American	0.0014%	71,554

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.Leu804Ser
Coding: c.2411T>C
MANE Select: NM_015230
Type: single nucleotide variant
Location: chr4:36160490 (GRCh38)
Gene constraint: LOEUF 0.884 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.42 · 2 PDB
Residue 804: the arf-gap 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-leu804ser (accessed [today's date]).

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