Is ADGRE2 p.Cys167Arg (c.499T>C) pathogenic?

ADGRE2 p.Cys167Arg (c.499T>C) is classified Conflicting classifications of pathogenicity in ADGRE2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-23). AlphaMissense: likely pathogenic (0.9513); Rare (popmax 0.489%, afr).

How common is ADGRE2 p.Cys167Arg (c.499T>C) in the general population?

ADGRE2 p.Cys167Arg (c.499T>C) is rare (popmax 0.489%, afr) (gnomAD).

What do computational predictors say about ADGRE2 p.Cys167Arg (c.499T>C)?

AlphaMissense predicts likely pathogenic (score 0.9513) — an in-silico prediction, not a clinical call.

ADGRE2 p.Cys167Arg

c.499T>C · rs149621907 · VCV3044484

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9513 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.489%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9513	likely pathogenic · top 1% in ADGRE2
REVEL	0.743	pathogenic-leaning
SaProt	LLR -14.77	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 1.8, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 756 bp · p 0.47 · regional, not allelic
Overall
CADD	23.3	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 0.489% African / African-American · 367/74,992 alleles

Filtering AF 0.448% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.432%

Overall 0.0532% 858/1,613,768 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.489%	204
Middle Eastern	0.271%	369
Admixed American	0.175%	571
Remaining individualsnot grpmax-eligible	0.0976%	1,024
European (non-Finnish)	0.0253%	3,960
South Asian	0.0121%	8,278

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.Cys167Arg
Coding: c.499T>C
MANE Select: NM_013447
dbSNP: rs149621907
Type: single nucleotide variant
Location: chr19:14766370 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.44 · 3 PDB
Residue 167: the egf-like 4; 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-cys167arg (accessed [today's date]).

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