Is ARAP2 p.Pro1233Ser (c.3697C>T) pathogenic?

ARAP2 p.Pro1233Ser (c.3697C>T) is classified Uncertain significance in ARAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-20). AlphaMissense: ambiguous (0.4607); Very rare (popmax 0.00268%, afr).

How common is ARAP2 p.Pro1233Ser (c.3697C>T) in the general population?

ARAP2 p.Pro1233Ser (c.3697C>T) is very rare (popmax 0.00268%, afr) (gnomAD).

What do computational predictors say about ARAP2 p.Pro1233Ser (c.3697C>T)?

AlphaMissense predicts ambiguous (score 0.4607) — an in-silico prediction, not a clinical call.

ARAP2 p.Pro1233Ser

c.3697C>T · rs748240394 · VCV2469310

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4607 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Computational evidence

Protein change
AlphaMissense	0.4607	ambiguous
REVEL	0.522	indeterminate
SaProt	LLR -8.81	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 162 kb · p 0.0019 · regional, not allelic
Overall
CADD	25.9	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 0.00268% African / African-American · 2/74,698 alleles

Filtering AF 0.00189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00211% 34/1,611,116 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00268%	37,349
European (non-Finnish)	0.00263%	38,009
Remaining individualsnot grpmax-eligible	0.0016%	62,336

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.Pro1233Ser
Coding: c.3697C>T
MANE Select: NM_015230
dbSNP: rs748240394
Type: single nucleotide variant
Location: chr4:36124911 (GRCh38)
Gene constraint: LOEUF 0.884 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.42 · 2 PDB
Residue 1233: the rho-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-pro1233ser (accessed [today's date]).

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