Is ADGRE2 p.Leu153Phe (c.457C>T) pathogenic?

ADGRE2 p.Leu153Phe (c.457C>T) is classified Uncertain significance in ADGRE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-01-15). AlphaMissense: likely benign (0.0586); Common (popmax 20%, afr) — too common for a highly-penetrant pathogenic allele; Associated with vibratory urticaria.

What condition is associated with ADGRE2 p.Leu153Phe (c.457C>T)?

ADGRE2 p.Leu153Phe (c.457C>T) is associated with vibratory urticaria (ClinVar).

What do computational predictors say about ADGRE2 p.Leu153Phe (c.457C>T)?

AlphaMissense predicts likely benign (score 0.0586) — an in-silico prediction, not a clinical call.

ADGRE2 p.Leu153Phe

Q: How common is ADGRE2 p.Leu153Phe (c.457C>T) in the general population?

ADGRE2 p.Leu153Phe (c.457C>T) is common (popmax 20%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.457C>T · rs12976493 · VCV1301601

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0586 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 20%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

vibratory urticaria

Computational evidence

Protein change
AlphaMissense	0.0586	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -10.36	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -3.6
Regional constraint	o/e 0.33	constrained · MANE · 105 bp · p 1.2e-05 · regional, not allelic
Overall
CADD	0.176	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 20% African / African-American · 5,926/29,664 alleles

Filtering AF 19.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 19.4%

Overall 2.87% 28,190/982,684 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	35.2%	3
African / African-Americangrpmax	20%	5
Admixed American	7.58%	13
Ashkenazi Jewishnot grpmax-eligible	6.5%	15
East Asian	4.99%	20
Finnishnot grpmax-eligible	4.72%	21
Middle Eastern	3.43%	29
Remaining individualsnot grpmax-eligible	2.19%	46
European (non-Finnish)	1.89%	53
South Asian	1.64%	61

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu153Phe
Coding: c.457C>T
MANE Select: NM_013447
dbSNP: rs12976493
Type: single nucleotide variant
Location: chr19:14767008 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.44 · 3 PDB
Residue 153: the egf-like 3; calcium-binding domain; a disulfide bond

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

Disease context

vibratory urticaria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ADGRE2 p.Ala307Val Benign/Likely benign ★★ ⚠ same condition
ADGRE2 p.Asn640Ser Benign/Likely benign ★★ same condition
ADGRE2 p.Leu614Phe Benign ★★ same condition
ADGRE2 p.Gln426Ter Likely pathogenic ★ same condition
ADGRE2 p.Ala415Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
ADGRE2 p.Asn165Ser Uncertain significance ★ ⚠ same condition
ADGRE2 p.Cys492Tyr Conflicting classifications of pathogenicity ★ ⚠ same condition
ADGRE2 p.Gly493Cys Uncertain significance ★ same condition

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-leu153phe (accessed [today's date]).

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