Is ADGRE2 p.Ser665Phe (c.1994C>T) pathogenic?

ADGRE2 p.Ser665Phe (c.1994C>T) is classified Benign in ADGRE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1582); Common (popmax 6.46%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ADGRE2 p.Ser665Phe (c.1994C>T)?

AlphaMissense predicts likely benign (score 0.1582) — an in-silico prediction, not a clinical call.

ADGRE2 p.Ser665Phe

Q: How common is ADGRE2 p.Ser665Phe (c.1994C>T) in the general population?

ADGRE2 p.Ser665Phe (c.1994C>T) is common (popmax 6.46%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1994C>T · rs3752187 · VCV2037579

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1582 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.46%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1582	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -6.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -2.7
Regional constraint	o/e 0.82	unconstrained · MANE · 29 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	13.58	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 6.46% East Asian · 2,898/44,886 alleles

Filtering AF 6.26% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.18%

Overall 1.08% 17,463/1,614,068 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	6.46%	15
South Asian	3%	33
Ashkenazi Jewishnot grpmax-eligible	2.54%	39
Finnishnot grpmax-eligible	1.95%	51
Amishnot grpmax-eligible	1.75%	57
Remaining individualsnot grpmax-eligible	1.5%	67
Middle Eastern	1.22%	82
African / African-American	0.7%	143
European (non-Finnish)	0.683%	146
Admixed American	0.375%	267

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.Ser665Phe
Coding: c.1994C>T
MANE Select: NM_013447
dbSNP: rs3752187
Type: single nucleotide variant
Location: chr19:14751466 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.44 · 3 PDB
Residue 665: a UniProt-annotated variant site (in)

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-ser665phe (accessed [today's date]).

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