Is ADGRE2 p.Arg46= (c.138C>A) pathogenic?

ADGRE2 p.Arg46= (c.138C>A) is classified Benign/Likely benign in ADGRE2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-25). Ultra-rare (popmax 0.0182%, nfe).

How common is ADGRE2 p.Arg46= (c.138C>A) in the general population?

ADGRE2 p.Arg46= (c.138C>A) is ultra-rare (popmax 0.0182%, nfe) (gnomAD).

ADGRE2 p.Arg46=

c.138C>A · rs202128202 · VCV1686348

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0182%, nfe)

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 -0.3	GERP 1.6
Overall
CADD	5.111	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0182% European (non-Finnish) · 215/1,180,044 alleles

Filtering AF 0.0162% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.0138% 223/1,614,060 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0182%	5,489
Remaining individualsnot grpmax-eligible	0.008%	12,497
Admixed American	0.00333%	29,998
African / African-American	0.00133%	74,918

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: ADGRE2
Protein: p.Arg46=
Coding: c.138C>A
MANE Select: NM_013447
dbSNP: rs202128202
Type: single nucleotide variant
Location: chr19:14773999 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.44 · 3 PDB
Residue 46: the egf-like 1 domain; a β-strand

Full ADGRE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADGRE2 p.Arg46Cys Uncertain significance ★ ⚠ same residue
ADGRE2 p.Arg46His Conflicting classifications of pathogenicity ★ ⚠ same residue
ADGRE2 p.Ala359Gly Uncertain significance ★★ ⚠ same type
ADGRE2 p.Ala44Thr Uncertain significance ★★ ⚠ same type
ADGRE2 p.Ala554Val Uncertain significance ★★ ⚠ same type
ADGRE2 p.Ala555Ser Uncertain significance ★★ ⚠ same type
ADGRE2 p.Ala589Thr Uncertain significance ★★ ⚠ same type
ADGRE2 p.Ala603Thr 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/adgre2-p-arg46 (accessed [today's date]).

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