Is ARHGAP35 p.Arg997Pro (c.2990G>C) pathogenic?

ARHGAP35 p.Arg997Pro (c.2990G>C) is classified Uncertain significance in ARHGAP35 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). AlphaMissense: likely benign (0.338); Ultra-rare (popmax 0.0516%, sas).

How common is ARHGAP35 p.Arg997Pro (c.2990G>C) in the general population?

ARHGAP35 p.Arg997Pro (c.2990G>C) is ultra-rare (popmax 0.0516%, sas) (gnomAD).

What do computational predictors say about ARHGAP35 p.Arg997Pro (c.2990G>C)?

AlphaMissense predicts likely benign (score 0.338) — an in-silico prediction, not a clinical call.

ARHGAP35 p.Arg997Pro

c.2990G>C · VCV4136681

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.338 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0516%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.338	likely benign
REVEL	0.229	benign-leaning
SaProt	LLR -4.97	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 10	GERP 2.6, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 17 kb · p 2.6e-07 · regional, not allelic
Overall
CADD	23.6	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 0.0516% South Asian · 47/91,074 alleles

Filtering AF 0.0399% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0357%

Overall 0.00644% 104/1,613,782 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0516%	1,938
Middle Eastern	0.0164%	6,084
European (non-Finnish)	0.00449%	22,262
Admixed American	0.00167%	59,980
Remaining individualsnot grpmax-eligible	0.0016%	62,464
Finnishnot grpmax-eligible	0.00156%	63,988

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: ARHGAP35
Protein: p.Arg997Pro
Coding: c.2990G>C
MANE Select: NM_004491
Type: single nucleotide variant
Location: chr19:46921665 (GRCh38)
Gene constraint: LOEUF 0.204 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.08 · 6 PDB

Full ARHGAP35 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP35 p.Arg1164= Benign ★★ same type
ARHGAP35 p.Leu125= Benign ★★ same type
ARHGAP35 p.Pro581= Benign ★★ same type
ARHGAP35 p.Arg109Ter Likely pathogenic ★ same type
ARHGAP35 p.Gln1067Ter Pathogenic ★ same type
ARHGAP35 p.Gln1352Ter Pathogenic ★ same type
ARHGAP35 p.Gln534Ter Likely pathogenic ★ same type
ARHGAP35 p.Lys118Ter Likely pathogenic ★ 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/arhgap35-p-arg997pro (accessed [today's date]).

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