Is ADGRE2 p.Val233Met (c.697G>A) pathogenic?

ADGRE2 p.Val233Met (c.697G>A) is classified Benign in ADGRE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). AlphaMissense: likely benign (0.1221); Ultra-rare (popmax 0.0111%, eas).

How common is ADGRE2 p.Val233Met (c.697G>A) in the general population?

ADGRE2 p.Val233Met (c.697G>A) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about ADGRE2 p.Val233Met (c.697G>A)?

AlphaMissense predicts likely benign (score 0.1221) — an in-silico prediction, not a clinical call.

ADGRE2 p.Val233Met

c.697G>A · rs377729863 · VCV1685941

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1221 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1221	likely benign
REVEL	0.324	indeterminate
SaProt	LLR -8.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -15	GERP -3.5
Regional constraint	o/e 0.29	constrained · MANE · 567 bp · p 1.3e-08 · regional, not allelic
Overall
CADD	0.112	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 0.0111% East Asian · 5/44,868 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00167% 27/1,613,054 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,974
African / African-American	0.00801%	12,481
South Asian	0.00769%	13,011
European (non-Finnish)	0.000763%	131,020

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.Val233Met
Coding: c.697G>A
MANE Select: NM_013447
dbSNP: rs377729863
Type: single nucleotide variant
Location: chr19:14765742 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.44 · 3 PDB
Residue 233: the egf-like 5; calcium-binding domain; a disulfide bond

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

Similar variants

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
ADGRE2 p.Ala656Thr Uncertain significance ★★ ⚠ same type
ADGRE2 p.Ala664Gly 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-val233met (accessed [today's date]).

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