Is ARHGAP35 p.Ser992Pro (c.2974T>C) pathogenic?

ARHGAP35 p.Ser992Pro (c.2974T>C) is classified Uncertain significance in ARHGAP35 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-21). AlphaMissense: likely benign (0.077); Ultra-rare (popmax 0.0214%, afr).

How common is ARHGAP35 p.Ser992Pro (c.2974T>C) in the general population?

ARHGAP35 p.Ser992Pro (c.2974T>C) is ultra-rare (popmax 0.0214%, afr) (gnomAD).

What do computational predictors say about ARHGAP35 p.Ser992Pro (c.2974T>C)?

AlphaMissense predicts likely benign (score 0.077) — an in-silico prediction, not a clinical call.

ARHGAP35 p.Ser992Pro

c.2974T>C · rs985258635 · VCV2403097

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.077 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0214%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.077	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -6.50	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 4.3	GERP -0.83, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 17 kb · p 2.6e-07 · regional, not allelic
Overall
CADD	17.15	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 0.0214% African / African-American · 16/74,906 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.00143% 23/1,613,840 alleles · ultra-rare exomes 23/1,461,710 · genomes 0/152,130 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0214%	4,682
Remaining individualsnot grpmax-eligible	0.0096%	10,411
European (non-Finnish)	8.48e-05%	1,179,896

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.Ser992Pro
Coding: c.2974T>C
MANE Select: NM_004491
dbSNP: rs985258635
Type: single nucleotide variant
Location: chr19:46921649 (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-ser992pro (accessed [today's date]).

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