Is ARHGEF1 p.Pro74= (c.222C>T) pathogenic?

ARHGEF1 p.Pro74= (c.222C>T) is classified Likely benign in ARHGEF1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-08). Very rare (popmax 0.005%, amr).

How common is ARHGEF1 p.Pro74= (c.222C>T) in the general population?

ARHGEF1 p.Pro74= (c.222C>T) is very rare (popmax 0.005%, amr) (gnomAD).

ARHGEF1 p.Pro74=

c.222C>T · rs201383072 · VCV1664666

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.029	GERP -3.1, phastCons 0.15
Overall
CADD	9.723	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,986 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00341% 55/1,613,406 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,995
Remaining individualsnot grpmax-eligible	0.0048%	20,817
European (non-Finnish)	0.00382%	26,211
South Asian	0.0033%	30,345
Finnishnot grpmax-eligible	0.00156%	63,998

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: ARHGEF1
Protein: p.Pro74=
Coding: c.222C>T
MANE Select: NM_004706
dbSNP: rs201383072
Type: single nucleotide variant
Location: chr19:41888862 (GRCh38)
Gene constraint: LOEUF 0.459 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.49 · 7 PDB
Residue 74: the rgsl domain; an α-helix

Full ARHGEF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGEF1 p.Pro74His Uncertain significance ★★ ⚠ same residue
ARHGEF1 p.Pro74Leu Uncertain significance ★★ ⚠ same residue
ARHGEF1 p.Pro74Thr Uncertain significance ★ ⚠ same residue
ARHGEF1 c.1738+5C>T Uncertain significance ★★ same type
ARHGEF1 c.644+6G>T Uncertain significance ★★ same type
ARHGEF1 c.-20+1180T>A Uncertain significance ★★ same type
ARHGEF1 c.-20+1201G>C Uncertain significance ★★ same type
ARHGEF1 p.Ala119Thr 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/arhgef1-p-pro74 (accessed [today's date]).

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