Is ADGRE2 p.Pro34His (c.101C>A) pathogenic?

ADGRE2 p.Pro34His (c.101C>A) is classified Uncertain significance in ADGRE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-18). AlphaMissense: ambiguous (0.4833); Very rare (popmax 0.00212%, nfe).

How common is ADGRE2 p.Pro34His (c.101C>A) in the general population?

ADGRE2 p.Pro34His (c.101C>A) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about ADGRE2 p.Pro34His (c.101C>A)?

AlphaMissense predicts ambiguous (score 0.4833) — an in-silico prediction, not a clinical call.

ADGRE2 p.Pro34His

c.101C>A · rs912959685 · VCV2728201

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4833 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4833	ambiguous
REVEL	0.539	indeterminate
SaProt	LLR -14.51	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 0.68, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 9,655 bp · p 0.17 · regional, not allelic
Overall
CADD	22.7	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 0.00212% European (non-Finnish) · 25/1,180,024 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00171% 25/1,461,828 alleles · very 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.Pro34His
Coding: c.101C>A
MANE Select: NM_013447
dbSNP: rs912959685
Type: single nucleotide variant
Location: chr19:14774036 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.44 · 3 PDB
Residue 34: the egf-like 1 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-pro34his (accessed [today's date]).

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