Is ADGRE5 p.Pro487Ser (c.1459C>T) pathogenic?

ADGRE5 p.Pro487Ser (c.1459C>T) is classified Uncertain significance in ADGRE5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-02). AlphaMissense: likely benign (0.1944); Very rare (popmax 0.00755%, nfe).

How common is ADGRE5 p.Pro487Ser (c.1459C>T) in the general population?

ADGRE5 p.Pro487Ser (c.1459C>T) is very rare (popmax 0.00755%, nfe) (gnomAD).

What do computational predictors say about ADGRE5 p.Pro487Ser (c.1459C>T)?

AlphaMissense predicts likely benign (score 0.1944) — an in-silico prediction, not a clinical call.

ADGRE5 p.Pro487Ser

c.1459C>T · VCV3497517

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1944 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00755%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1944	likely benign
REVEL	0.15	moderately benign-leaning
SaProt	LLR -6.13	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 -0.053
Regional constraint	o/e 1.02	unconstrained · MANE · 2,993 bp · p 0.81 · regional, not allelic
Overall
CADD	8.564	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 0.00755% European (non-Finnish) · 89/1,178,700 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00578% 93/1,609,058 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00755%	13,244
Remaining individualsnot grpmax-eligible	0.00481%	20,777
African / African-American	0.00134%	74,814

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: ADGRE5
Protein: p.Pro487Ser
Coding: c.1459C>T
MANE Select: NM_078481
Type: single nucleotide variant
Location: chr19:14404392 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.39 · 9 PDB
Residue 487: the gain-b domain; an α-helix

Full ADGRE5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADGRE5 c.1183+10G>A Benign ★★ same type
ADGRE5 p.Asn371= Benign ★★ same type
ADGRE5 p.Ile666Met Likely benign ★★ ⚠ same type
ADGRE5 p.Leu635= Benign ★★ same type
ADGRE5 p.Ala379Thr Uncertain significance ★ ⚠ same type
ADGRE5 p.Ala388Ser Uncertain significance ★ ⚠ same type
ADGRE5 p.Ala39Thr Uncertain significance ★ ⚠ same type
ADGRE5 p.Ala412Pro 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/adgre5-p-pro487ser (accessed [today's date]).

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