Is ARHGAP6 p.Ser763Pro (c.2287T>C) pathogenic?

ARHGAP6 p.Ser763Pro (c.2287T>C) is classified Uncertain significance in ARHGAP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-25). AlphaMissense: likely benign (0.0837); Very rare (popmax 0.000116%, nfe); Associated with neurodevelopmental disorder.

What condition is associated with ARHGAP6 p.Ser763Pro (c.2287T>C)?

ARHGAP6 p.Ser763Pro (c.2287T>C) is associated with neurodevelopmental disorder (ClinVar).

How common is ARHGAP6 p.Ser763Pro (c.2287T>C) in the general population?

ARHGAP6 p.Ser763Pro (c.2287T>C) is very rare (popmax 0.000116%, nfe) (gnomAD).

What do computational predictors say about ARHGAP6 p.Ser763Pro (c.2287T>C)?

AlphaMissense predicts likely benign (score 0.0837) — an in-silico prediction, not a clinical call.

ARHGAP6 p.Ser763Pro

c.2287T>C · VCV3383302

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0837 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000116%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.0837	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -6.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 647 bp · p 0.82 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000116% European (non-Finnish) · 1/864,977 alleles

Overall 9.72e-05% 1/1,028,518 alleles · very rare

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: ARHGAP6
Protein: p.Ser763Pro
Coding: c.2287T>C
MANE Select: NM_013427
Type: single nucleotide variant
Location: chrX:11139501 (GRCh38)
Structure: AlphaFold pLDDT 56.60
Residue 763: the 'disordered' region

Full ARHGAP6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ARHGAP6 p.Ala589Thr Likely benign ★ same condition
ARHGAP6 c.589-9G>T Likely benign ★★ same type
ARHGAP6 p.Ala533= Benign ★★ same type
ARHGAP6 p.Leu413= Benign ★★ same type
ARHGAP6 p.Leu526= Benign ★★ same type
ARHGAP6 p.Leu841= Benign ★★ same type
ARHGAP6 p.Tyr190= Benign ★★ same type
HCCS c.521+7A>G Benign/Likely benign ★★ 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/arhgap6-p-ser763pro (accessed [today's date]).

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