Is ADGRE2 p.Leu445Pro (c.1334T>C) pathogenic?

ADGRE2 p.Leu445Pro (c.1334T>C) is classified Uncertain significance in ADGRE2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-06). AlphaMissense: ambiguous (0.5181); Ultra-rare (popmax 0.0533%, afr).

How common is ADGRE2 p.Leu445Pro (c.1334T>C) in the general population?

ADGRE2 p.Leu445Pro (c.1334T>C) is ultra-rare (popmax 0.0533%, afr) (gnomAD).

What do computational predictors say about ADGRE2 p.Leu445Pro (c.1334T>C)?

AlphaMissense predicts ambiguous (score 0.5181) — an in-silico prediction, not a clinical call.

ADGRE2 p.Leu445Pro

c.1334T>C · rs146325095 · VCV2186585

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5181 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0533%, afr)

Computational evidence

Protein change
AlphaMissense	0.5181	ambiguous
REVEL	0.598	indeterminate
SaProt	LLR -13.25	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.5, phastCons 0.21
Regional constraint	o/e 0.82	unconstrained · MANE · 29 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	20.7	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 0.0533% African / African-American · 40/75,038 alleles

Filtering AF 0.0401% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0356%

Overall 0.00248% 40/1,614,186 alleles · ultra-rare

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.Leu445Pro
Coding: c.1334T>C
MANE Select: NM_013447
dbSNP: rs146325095
Type: single nucleotide variant
Location: chr19:14755736 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.44 · 3 PDB
Residue 445: the gain-b domain

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-leu445pro (accessed [today's date]).

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