Is ADGRE2 p.Ser83Leu (c.248C>T) pathogenic?

ADGRE2 p.Ser83Leu (c.248C>T) is classified Conflicting classifications of pathogenicity in ADGRE2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-05-14). AlphaMissense: likely benign (0.2852); Ultra-rare (popmax 0.0156%, eas).

How common is ADGRE2 p.Ser83Leu (c.248C>T) in the general population?

ADGRE2 p.Ser83Leu (c.248C>T) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about ADGRE2 p.Ser83Leu (c.248C>T)?

AlphaMissense predicts likely benign (score 0.2852) — an in-silico prediction, not a clinical call.

ADGRE2 p.Ser83Leu

c.248C>T · rs201617124 · VCV1686326

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2852 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2852	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -11.65	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.41	GERP -0.39
Regional constraint	o/e 0.89	unconstrained · MANE · 9,655 bp · p 0.17 · regional, not allelic
Overall
CADD	16.81	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 0.0156% East Asian · 7/44,872 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.0018% 29/1,613,944 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,410
Admixed American	0.00834%	11,997
African / African-American	0.00267%	37,469
South Asian	0.0022%	45,530
Remaining individualsnot grpmax-eligible	0.0016%	62,502
European (non-Finnish)	0.00102%	98,333

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.Ser83Leu
Coding: c.248C>T
MANE Select: NM_013447
dbSNP: rs201617124
Type: single nucleotide variant
Location: chr19:14772449 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.44 · 3 PDB
Residue 83: the egf-like 2; calcium-binding domain; a disulfide bond; a β-strand

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

Similar variants

ADGRE2 p.Ser83= Benign ★ 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
ADGRE2 p.Ala656Thr 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-ser83leu (accessed [today's date]).

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