Is ARHGAP26 p.Pro657His (c.1970C>A) pathogenic?

ARHGAP26 p.Pro657His (c.1970C>A) is classified Uncertain significance in ARHGAP26 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: likely benign (0.1004); Ultra-rare (popmax 0.0307%, afr).

How common is ARHGAP26 p.Pro657His (c.1970C>A) in the general population?

ARHGAP26 p.Pro657His (c.1970C>A) is ultra-rare (popmax 0.0307%, afr) (gnomAD).

What do computational predictors say about ARHGAP26 p.Pro657His (c.1970C>A)?

AlphaMissense predicts likely benign (score 0.1004) — an in-silico prediction, not a clinical call.

ARHGAP26 p.Pro657His

c.1970C>A · rs142158613 · VCV2347655

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1004 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1004	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -7.16	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 2.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 88 kb · p 0.1 · regional, not allelic
Overall
CADD	22.0	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 0.0307% African / African-American · 23/74,906 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.00186% 30/1,613,588 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0307%	3,257
Middle Eastern	0.0164%	6,080
Remaining individualsnot grpmax-eligible	0.0064%	15,619
Admixed American	0.00167%	59,966
South Asian	0.0011%	91,030

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.Pro657His
Coding: c.1970C>A
MANE Select: NM_001135608
dbSNP: rs142158613
Type: single nucleotide variant
Location: chr5:143147363 (GRCh38)
Gene constraint: LOEUF 0.493 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 78.09 · 1 PDB
Residue 657: 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-pro657his (accessed [today's date]).

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