Is ARHGAP26 p.Ser591Phe (c.1772C>T) pathogenic?

ARHGAP26 p.Ser591Phe (c.1772C>T) is classified Uncertain significance in ARHGAP26 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: likely benign (0.1476); Very rare (popmax 0.00133%, afr).

How common is ARHGAP26 p.Ser591Phe (c.1772C>T) in the general population?

ARHGAP26 p.Ser591Phe (c.1772C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ARHGAP26 p.Ser591Phe (c.1772C>T)?

AlphaMissense predicts likely benign (score 0.1476) — an in-silico prediction, not a clinical call.

ARHGAP26 p.Ser591Phe

c.1772C>T · VCV4642299

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1476 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1476	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -8.48	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 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 88 kb · p 0.1 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00133% African / African-American · 1/75,040 alleles

Overall 6.84e-05% 1/1,461,168 alleles · very rare

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.Ser591Phe
Coding: c.1772C>T
MANE Select: NM_001135608
Type: single nucleotide variant
Location: chr5:143134040 (GRCh38)
Gene constraint: LOEUF 0.493 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 78.09 · 1 PDB

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-ser591phe (accessed [today's date]).

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