Is ADGRE2 p.Phe12Leu (c.36C>G) pathogenic?

ADGRE2 p.Phe12Leu (c.36C>G) is classified Uncertain significance in ADGRE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-11). AlphaMissense: ambiguous (0.3887); Very rare (popmax 0.00812%, afr).

How common is ADGRE2 p.Phe12Leu (c.36C>G) in the general population?

ADGRE2 p.Phe12Leu (c.36C>G) is very rare (popmax 0.00812%, afr) (gnomAD).

What do computational predictors say about ADGRE2 p.Phe12Leu (c.36C>G)?

AlphaMissense predicts ambiguous (score 0.3887) — an in-silico prediction, not a clinical call.

ADGRE2 p.Phe12Leu

c.36C>G · rs955908891 · VCV2791876

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3887 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00812%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3887	ambiguous
REVEL	0.04	moderately benign-leaning
SaProt	LLR -4.42	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5	GERP -2
Regional constraint	o/e 0.89	unconstrained · MANE · 9,655 bp · p 0.17 · regional, not allelic
Overall
CADD	0.067	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 0.00812% African / African-American · 6/73,924 alleles

Filtering AF 0.00351% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.000443% 7/1,578,376 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00812%	12,321
Remaining individualsnot grpmax-eligible	0.00164%	60,950

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.Phe12Leu
Coding: c.36C>G
MANE Select: NM_013447
dbSNP: rs955908891
Type: single nucleotide variant
Location: chr19:14774302 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.44 · 3 PDB

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-phe12leu (accessed [today's date]).

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