Is ADGRE1 p.Phe545Ser (c.1634T>C) pathogenic?

ADGRE1 p.Phe545Ser (c.1634T>C) is classified Uncertain significance in ADGRE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-22). AlphaMissense: likely benign (0.0711); Very rare (popmax 0.00187%, nfe).

How common is ADGRE1 p.Phe545Ser (c.1634T>C) in the general population?

ADGRE1 p.Phe545Ser (c.1634T>C) is very rare (popmax 0.00187%, nfe) (gnomAD).

What do computational predictors say about ADGRE1 p.Phe545Ser (c.1634T>C)?

AlphaMissense predicts likely benign (score 0.0711) — an in-silico prediction, not a clinical call.

ADGRE1 p.Phe545Ser

c.1634T>C · VCV4829855

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0711 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00187%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0711	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -2.78	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 -3.8	GERP -3.1
Regional constraint	o/e 0.95	unconstrained · MANE · 52 kb · p 0.11 · regional, not allelic
Overall
CADD	0.289	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00187% European (non-Finnish) · 22/1,175,494 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00105%

Overall 0.00138% 22/1,599,446 alleles · very rare

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: ADGRE1
Protein: p.Phe545Ser
Coding: c.1634T>C
MANE Select: NM_001974
Type: single nucleotide variant
Location: chr19:6921726 (GRCh38)
Gene constraint: LOEUF 0.951 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.75
Residue 545: the gain-b domain

Full ADGRE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADGRE1 c.2382-4C>T Benign ★★ same type
ADGRE1 p.Arg2Leu Benign ★★ same type
ADGRE1 p.Pro880Thr Benign ★★ same type
ADGRE1 p.Thr885Met Benign ★★ ⚠ same type
ADGRE1 p.Ala177Val Uncertain significance ★ ⚠ same type
ADGRE1 p.Ala57Val Uncertain significance ★ ⚠ same type
ADGRE1 p.Ala592Val Uncertain significance ★ ⚠ same type
ADGRE1 p.Ala620Val 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/adgre1-p-phe545ser (accessed [today's date]).

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