Is ARFGEF2 p.Pro880= (c.2640G>A) pathogenic?

ARFGEF2 p.Pro880= (c.2640G>A) is classified Conflicting classifications of pathogenicity in ARFGEF2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2022-11-22). Ultra-rare (popmax 0.0157%, nfe); Associated with periventricular heterotopia with microcephaly, autosomal recessive.

What condition is associated with ARFGEF2 p.Pro880= (c.2640G>A)?

ARFGEF2 p.Pro880= (c.2640G>A) is associated with periventricular heterotopia with microcephaly, autosomal recessive (ClinVar).

How common is ARFGEF2 p.Pro880= (c.2640G>A) in the general population?

ARFGEF2 p.Pro880= (c.2640G>A) is ultra-rare (popmax 0.0157%, nfe) (gnomAD).

ARFGEF2 p.Pro880=

c.2640G>A · rs368844677 · VCV434282

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0157%, nfe)

Conditions

periventricular heterotopia with microcephaly, autosomal recessive

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 -15	GERP -4.8
Overall
CADD	0.039	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0157% European (non-Finnish) · 185/1,180,026 alleles

Filtering AF 0.0138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0131%

Overall 0.0129% 209/1,614,068 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0157%	6,379
Remaining individualsnot grpmax-eligible	0.0128%	7,810
Finnishnot grpmax-eligible	0.00781%	12,806
African / African-American	0.00667%	14,986
Admixed American	0.005%	20,001
South Asian	0.00329%	30,363

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: ARFGEF2
Protein: p.Pro880=
Coding: c.2640G>A
MANE Select: NM_006420
dbSNP: rs368844677
Type: single nucleotide variant
Location: chr20:48989391 (GRCh38)
Gene constraint: LOEUF 0.391 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.59 · 2 PDB

Full ARFGEF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

periventricular heterotopia with microcephaly, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ARFGEF2 p.Pro880fs Pathogenic ★ same residue
ARFGEF2 p.Pro880Leu Uncertain significance ★★ ⚠ same residue
ARFGEF2 c.4315+5T>G Uncertain significance ★★ same condition
ARFGEF2 c.4316-12T>C Uncertain significance ★★ same condition
ARFGEF2 c.*368A>G Uncertain significance ★★ same condition
ARFGEF2 p.Arg1092Cys Uncertain significance ★★ ⚠ same condition
ARFGEF2 p.Arg113Gln Uncertain significance ★★ ⚠ same condition
ARFGEF2 p.Arg1509His Uncertain significance ★★ ⚠ same condition

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/arfgef2-p-pro880 (accessed [today's date]).

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