Is ARHGAP24 p.Ser462Arg (c.1386C>A) pathogenic?

ARHGAP24 p.Ser462Arg (c.1386C>A) is classified Conflicting classifications of pathogenicity in ARHGAP24 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-12). AlphaMissense: likely pathogenic (0.5812); Ultra-rare (popmax 0.0319%, nfe).

How common is ARHGAP24 p.Ser462Arg (c.1386C>A) in the general population?

ARHGAP24 p.Ser462Arg (c.1386C>A) is ultra-rare (popmax 0.0319%, nfe) (gnomAD).

What do computational predictors say about ARHGAP24 p.Ser462Arg (c.1386C>A)?

AlphaMissense predicts likely pathogenic (score 0.5812) — an in-silico prediction, not a clinical call.

ARHGAP24 p.Ser462Arg

c.1386C>A · rs142672228 · VCV2194575

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5812 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0319%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5812	likely pathogenic
REVEL	0.027	moderately benign-leaning
SaProt	LLR -8.10	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.39	GERP 6.8, phastCons 0.99
Regional constraint	o/e 1.02	unconstrained · MANE · 430 kb · p 0.6 · regional, not allelic
Overall
CADD	19.3	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 0.0319% European (non-Finnish) · 376/1,180,030 alleles

Filtering AF 0.0292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0281%

Overall 0.0253% 408/1,613,948 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0319%	3,138
Finnishnot grpmax-eligible	0.0312%	3,200
Remaining individualsnot grpmax-eligible	0.016%	6,248
African / African-American	0.00267%	37,442

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: ARHGAP24
Protein: p.Ser462Arg
Coding: c.1386C>A
MANE Select: NM_001025616
dbSNP: rs142672228
Type: single nucleotide variant
Location: chr4:85995040 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.68
Residue 462: the 'disordered' region

Full ARHGAP24 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP24 p.Arg39His Uncertain significance ★★ ⚠ same type
ARHGAP24 p.Arg483Cys Uncertain significance ★★ ⚠ same type
ARHGAP24 p.Arg93Ter Uncertain significance ★★ same type
ARHGAP24 p.Arg95Gln Uncertain significance ★★ ⚠ same type
ARHGAP24 p.Asn454Ser Uncertain significance ★★ ⚠ same type
ARHGAP24 p.Asn587Ile Uncertain significance ★★ ⚠ same type
ARHGAP24 p.Asp55Val Uncertain significance ★★ ⚠ same type
ARHGAP24 p.Gln158Arg 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/arhgap24-p-ser462arg (accessed [today's date]).

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