Is ARHGAP44 p.Ala553Pro (c.1657G>C) pathogenic?

ARHGAP44 p.Ala553Pro (c.1657G>C) is classified Uncertain significance in ARHGAP44 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-20). AlphaMissense: likely benign (0.0606); Ultra-rare (popmax 0.0196%, eas).

How common is ARHGAP44 p.Ala553Pro (c.1657G>C) in the general population?

ARHGAP44 p.Ala553Pro (c.1657G>C) is ultra-rare (popmax 0.0196%, eas) (gnomAD).

What do computational predictors say about ARHGAP44 p.Ala553Pro (c.1657G>C)?

AlphaMissense predicts likely benign (score 0.0606) — an in-silico prediction, not a clinical call.

ARHGAP44 p.Ala553Pro

c.1657G>C · rs2039607460 · VCV3128873

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0606 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0196%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0606	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -4.66	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 0.12	GERP 0.35, phastCons 0.001
Regional constraint	o/e 1.04	unconstrained · MANE · 16 kb · p 0.47 · regional, not allelic
Overall
CADD	14.46	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 0.0196% East Asian · 8/40,912 alleles

Filtering AF 0.00967% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00704%

Overall 0.000716% 10/1,395,888 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0196%	5,114
Remaining individualsnot grpmax-eligible	0.00167%	59,878
African / African-American	0.00137%	73,088

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.Ala553Pro
Coding: c.1657G>C
MANE Select: NM_014859
dbSNP: rs2039607460
Type: single nucleotide variant
Location: chr17:12974204 (GRCh38)
Gene constraint: LOEUF 0.605 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.39
Residue 553: 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-ala553pro (accessed [today's date]).

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