Is ARHGAP28 p.Arg421Gln (c.1262G>A) pathogenic?

ARHGAP28 p.Arg421Gln (c.1262G>A) is classified Uncertain significance in ARHGAP28 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-17). AlphaMissense: likely pathogenic (0.9796); Very rare (popmax 0.00329%, sas).

How common is ARHGAP28 p.Arg421Gln (c.1262G>A) in the general population?

ARHGAP28 p.Arg421Gln (c.1262G>A) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about ARHGAP28 p.Arg421Gln (c.1262G>A)?

AlphaMissense predicts likely pathogenic (score 0.9796) — an in-silico prediction, not a clinical call.

ARHGAP28 p.Arg421Gln

c.1262G>A · VCV3939815

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9796 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9796	likely pathogenic · top 5% in ARHGAP28
REVEL	0.478	indeterminate
SaProt	LLR -9.66	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.27 · evaluated, not missing
Pangolin	Δ0.28	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 12	GERP 6.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 182 kb · p 0.29 · regional, not allelic
Overall
CADD	33.0	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 0.00329% South Asian · 3/91,060 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00041% 6/1,461,756 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,353
East Asian	0.00223%	44,852
Admixed American	0.00167%	60,016
European (non-Finnish)	8.47e-05%	1,179,948

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: ARHGAP28
Protein: p.Arg421Gln
Coding: c.1262G>A
MANE Select: NM_001366230
Type: single nucleotide variant
Location: chr18:6876180 (GRCh38)
Gene constraint: LOEUF 0.796 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.63
Residue 421: the rho-gap domain; a functional site (arginine finger; crucial for gtp hydrolysis by stabilizing the transition state)

Full ARHGAP28 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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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/arhgap28-p-arg421gln (accessed [today's date]).

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