Is ARHGAP44 p.Pro656Ala (c.1966C>G) pathogenic?

ARHGAP44 p.Pro656Ala (c.1966C>G) is classified Uncertain significance in ARHGAP44 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-01). AlphaMissense: likely benign (0.0694); Very rare (popmax 0.000525%, nfe).

How common is ARHGAP44 p.Pro656Ala (c.1966C>G) in the general population?

ARHGAP44 p.Pro656Ala (c.1966C>G) is very rare (popmax 0.000525%, nfe) (gnomAD).

What do computational predictors say about ARHGAP44 p.Pro656Ala (c.1966C>G)?

AlphaMissense predicts likely benign (score 0.0694) — an in-silico prediction, not a clinical call.

ARHGAP44 p.Pro656Ala

c.1966C>G · rs767230501 · VCV2471428

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0694 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000525%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0694	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	LLR -10.98	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 16 kb · p 0.47 · regional, not allelic
Overall
CADD	23.5	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 0.000525% European (non-Finnish) · 6/1,143,100 alleles

Filtering AF 0.000189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000124%

Overall 0.000456% 7/1,534,520 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0017%	58,946
European (non-Finnish)grpmax	0.000525%	190,517

Remaining individuals 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: ARHGAP44
Protein: p.Pro656Ala
Coding: c.1966C>G
MANE Select: NM_014859
dbSNP: rs767230501
Type: single nucleotide variant
Location: chr17:12984557 (GRCh38)
Gene constraint: LOEUF 0.605 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.39
Residue 656: the 'disordered' region

Full ARHGAP44 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP44 p.Gln414= Benign ★★ same type
ARHGAP44 c.198+1G>A Uncertain significance ★ same type
ARHGAP44 p.Ala128Val Uncertain significance ★ ⚠ same type
ARHGAP44 p.Ala172Val Uncertain significance ★ ⚠ same type
ARHGAP44 p.Ala186Thr Uncertain significance ★ ⚠ same type
ARHGAP44 p.Ala304Val Uncertain significance ★ ⚠ same type
ARHGAP44 p.Ala366Thr Uncertain significance ★ ⚠ same type
ARHGAP44 p.Ala526Val 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/arhgap44-p-pro656ala (accessed [today's date]).

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