Is ARHGAP26 p.Leu663= (c.1989C>T) pathogenic?

ARHGAP26 p.Leu663= (c.1989C>T) is classified Likely benign in ARHGAP26 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-19). Ultra-rare (popmax 0.0434%, amr).

How common is ARHGAP26 p.Leu663= (c.1989C>T) in the general population?

ARHGAP26 p.Leu663= (c.1989C>T) is ultra-rare (popmax 0.0434%, amr) (gnomAD).

ARHGAP26 p.Leu663=

c.1989C>T · VCV3890422

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0434%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.11	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Overall
CADD	19.11	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0434% Admixed American · 26/59,884 alleles

Filtering AF 0.0304% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.0044% 71/1,612,172 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0434%	2,303
Remaining individualsnot grpmax-eligible	0.00641%	15,602
European (non-Finnish)	0.00339%	29,472
African / African-American	0.00134%	74,790

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: ARHGAP26
Protein: p.Leu663=
Coding: c.1989C>T
MANE Select: NM_001135608
Type: single nucleotide variant
Location: chr5:143207198 (GRCh38)
Gene constraint: LOEUF 0.493 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 78.09 · 1 PDB
Residue 663: the 'disordered' region

Full ARHGAP26 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP26 c.2099+147C>T Uncertain significance ★ ⚠ same type
ARHGAP26 c.2099+149G>A Uncertain significance ★ ⚠ same type
ARHGAP26 c.2099+38G>C Uncertain significance ★ ⚠ same type
ARHGAP26 c.2099+93A>G Uncertain significance ★ ⚠ same type
ARHGAP26 p.Ala126Thr Uncertain significance ★ ⚠ same type
ARHGAP26 p.Ala163Ser Uncertain significance ★ ⚠ same type
ARHGAP26 p.Ala477Thr Uncertain significance ★ ⚠ same type
ARHGAP26 p.Ala56Val 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/arhgap26-p-leu663 (accessed [today's date]).

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