Is ADGRE2 p.Thr168Pro (c.502A>C) pathogenic?

ADGRE2 p.Thr168Pro (c.502A>C) is classified Uncertain significance in ADGRE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-26). AlphaMissense: likely benign (0.1599); Ultra-rare (popmax 0.0617%, amr).

How common is ADGRE2 p.Thr168Pro (c.502A>C) in the general population?

ADGRE2 p.Thr168Pro (c.502A>C) is ultra-rare (popmax 0.0617%, amr) (gnomAD).

What do computational predictors say about ADGRE2 p.Thr168Pro (c.502A>C)?

AlphaMissense predicts likely benign (score 0.1599) — an in-silico prediction, not a clinical call.

ADGRE2 p.Thr168Pro

c.502A>C · VCV3270980

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1599 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0617%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1599	likely benign
REVEL	0.409	indeterminate
SaProt	LLR -11.36	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 -11	GERP -3.6
Regional constraint	o/e 0.92	unconstrained · MANE · 756 bp · p 0.47 · regional, not allelic
Overall
CADD	6.175	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 0.0617% Admixed American · 37/59,948 alleles

Filtering AF 0.046% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0405%

Overall 0.00242% 39/1,613,534 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0617%	1,620
Remaining individualsnot grpmax-eligible	0.0016%	62,448
European (non-Finnish)	8.47e-05%	1,179,976

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.Thr168Pro
Coding: c.502A>C
MANE Select: NM_013447
Type: single nucleotide variant
Location: chr19:14766367 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.44 · 3 PDB
Residue 168: 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.Thr168Asn Uncertain significance ★ ⚠ 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-thr168pro (accessed [today's date]).

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