Is ARHGAP1 p.Arg69Trp (c.205C>T) pathogenic?

ARHGAP1 p.Arg69Trp (c.205C>T) is classified Conflicting classifications of pathogenicity in ARHGAP1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2021-09-16). AlphaMissense: likely pathogenic (0.7563); Rare (popmax 0.239%, amr).

How common is ARHGAP1 p.Arg69Trp (c.205C>T) in the general population?

ARHGAP1 p.Arg69Trp (c.205C>T) is rare (popmax 0.239%, amr) (gnomAD).

What do computational predictors say about ARHGAP1 p.Arg69Trp (c.205C>T)?

AlphaMissense predicts likely pathogenic (score 0.7563) — an in-silico prediction, not a clinical call.

ARHGAP1 p.Arg69Trp

c.205C>T · rs760960194 · VCV722022

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7563 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.239%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7563	likely pathogenic
REVEL	0.335	indeterminate
SaProt	LLR -12.37	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 17 kb · p 0.00064 · regional, not allelic
Overall
CADD	25.2	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 0.239% Admixed American · 122/51,012 alleles

Filtering AF 0.205% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.192%

Overall 0.00896% 139/1,551,878 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.239%	418
Middle Eastern	0.0167%	5,994
South Asian	0.00595%	16,815
Remaining individualsnot grpmax-eligible	0.00499%	20,048
European (non-Finnish)	0.000697%	143,382

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: ARHGAP1
Protein: p.Arg69Trp
Coding: c.205C>T
MANE Select: NM_004308
dbSNP: rs760960194
Type: single nucleotide variant
Location: chr11:46695684 (GRCh38)
Gene constraint: LOEUF 0.601 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 82.64 · 11 PDB
Residue 69: the cral-trio domain

Full ARHGAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP1 p.Leu263Phe Benign ★★ same type
ARHGAP1 p.Pro52= Benign ★★ same type
ARHGAP1 p.Ala225Ser Uncertain significance ★ ⚠ same type
ARHGAP1 p.Ala26Val Uncertain significance ★ ⚠ same type
ARHGAP1 p.Ala373Thr Uncertain significance ★ ⚠ same type
ARHGAP1 p.Ala68Pro Uncertain significance ★ ⚠ same type
ARHGAP1 p.Arg234Gln Uncertain significance ★ ⚠ same type
ARHGAP1 p.Arg234Trp 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/arhgap1-p-arg69trp (accessed [today's date]).

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