Is ARHGAP24 p.Pro417Leu (c.1250C>T) pathogenic?

ARHGAP24 p.Pro417Leu (c.1250C>T) is classified Conflicting classifications of pathogenicity in ARHGAP24 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-03-01). AlphaMissense: likely benign (0.1135); Very rare (popmax 0.00686%, nfe).

How common is ARHGAP24 p.Pro417Leu (c.1250C>T) in the general population?

ARHGAP24 p.Pro417Leu (c.1250C>T) is very rare (popmax 0.00686%, nfe) (gnomAD).

What do computational predictors say about ARHGAP24 p.Pro417Leu (c.1250C>T)?

AlphaMissense predicts likely benign (score 0.1135) — an in-silico prediction, not a clinical call.

ARHGAP24 p.Pro417Leu

c.1250C>T · rs756950646 · VCV2229468

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1135 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00686%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1135	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -6.41	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 7.7	GERP 5.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 430 kb · p 0.6 · regional, not allelic
Overall
CADD	24.5	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 0.00686% European (non-Finnish) · 81/1,180,014 alleles

Filtering AF 0.00563% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00861% 139/1,613,970 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0812%	1,231
European (non-Finnish)grpmax	0.00686%	14,568
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Admixed American	0.00167%	59,994
African / African-American	0.00134%	74,882
South Asian	0.0011%	91,086

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro417Leu
Coding: c.1250C>T
MANE Select: NM_001025616
dbSNP: rs756950646
Type: single nucleotide variant
Location: chr4:85994904 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.68
Residue 417: the 'disordered' region

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

Similar variants

ARHGAP24 p.Pro417Ala Benign/Likely benign ★★ same residue
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

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-pro417leu (accessed [today's date]).

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