Is ARHGAP24 p.Phe41Leu (c.123T>G) pathogenic?

ARHGAP24 p.Phe41Leu (c.123T>G) is classified Uncertain significance in ARHGAP24 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely pathogenic (0.9995); Very rare (popmax 0.00549%, sas).

How common is ARHGAP24 p.Phe41Leu (c.123T>G) in the general population?

ARHGAP24 p.Phe41Leu (c.123T>G) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about ARHGAP24 p.Phe41Leu (c.123T>G)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

ARHGAP24 p.Phe41Leu

c.123T>G · VCV4134698

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic · top 2% in ARHGAP24
REVEL	0.343	indeterminate
SaProt	LLR -12.40	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP 0.16, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 430 kb · p 0.6 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00549% South Asian · 5/91,076 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000558% 9/1,614,004 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,215
African / African-American	0.004%	24,972
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Phe41Leu
Coding: c.123T>G
MANE Select: NM_001025616
Type: single nucleotide variant
Location: chr4:85570664 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.68
Residue 41: the ph domain

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-phe41leu (accessed [today's date]).

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