Is ADGRE5 p.Pro461Ser (c.1381C>T) pathogenic?

ADGRE5 p.Pro461Ser (c.1381C>T) is classified Uncertain significance in ADGRE5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-08). AlphaMissense: likely benign (0.1691); Very rare (popmax 8.47e-05%, nfe).

How common is ADGRE5 p.Pro461Ser (c.1381C>T) in the general population?

ADGRE5 p.Pro461Ser (c.1381C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ADGRE5 p.Pro461Ser (c.1381C>T)?

AlphaMissense predicts likely benign (score 0.1691) — an in-silico prediction, not a clinical call.

ADGRE5 p.Pro461Ser

c.1381C>T · VCV3497526

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1691 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1691	likely benign
REVEL	0.171	moderately benign-leaning
SaProt	LLR -7.14	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 0.15
Regional constraint	o/e 1.02	unconstrained · MANE · 2,993 bp · p 0.81 · regional, not allelic
Overall
CADD	12.89	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 8.47e-05% European (non-Finnish) · 1/1,180,028 alleles

Overall 0.00149% 24/1,613,984 alleles · very rare exomes 20/1,461,862 · genomes 4/152,122 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0676%	1,480
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)grpmax	8.47e-05%	1,180,027

Ashkenazi Jewish 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: ADGRE5
Protein: p.Pro461Ser
Coding: c.1381C>T
MANE Select: NM_078481
Type: single nucleotide variant
Location: chr19:14402794 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.39 · 9 PDB
Residue 461: the gain-b domain

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-pro461ser (accessed [today's date]).

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