Is ARAP2 p.Asn697Lys (c.2091C>G) pathogenic?

ARAP2 p.Asn697Lys (c.2091C>G) is classified Uncertain significance in ARAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-27). AlphaMissense: likely pathogenic (0.9993); Very rare (popmax 0.00195%, nfe).

How common is ARAP2 p.Asn697Lys (c.2091C>G) in the general population?

ARAP2 p.Asn697Lys (c.2091C>G) is very rare (popmax 0.00195%, nfe) (gnomAD).

What do computational predictors say about ARAP2 p.Asn697Lys (c.2091C>G)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

ARAP2 p.Asn697Lys

c.2091C>G · VCV3419551

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic · top 1% in ARAP2
REVEL	0.653	pathogenic-leaning
SaProt	LLR -15.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 1.2, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 162 kb · p 0.0019 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00195% European (non-Finnish) · 23/1,179,970 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00149% 24/1,613,996 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,303
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Asn697Lys
Coding: c.2091C>G
MANE Select: NM_015230
Type: single nucleotide variant
Location: chr4:36164996 (GRCh38)
Gene constraint: LOEUF 0.884 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.42 · 2 PDB
Residue 697: 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-asn697lys (accessed [today's date]).

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