Is ADGRE3 p.Trp612Cys (c.1836G>T) pathogenic?

ADGRE3 p.Trp612Cys (c.1836G>T) is classified Uncertain significance in ADGRE3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-25). AlphaMissense: likely benign (0.3283); Very rare (popmax 0.00669%, eas).

How common is ADGRE3 p.Trp612Cys (c.1836G>T) in the general population?

ADGRE3 p.Trp612Cys (c.1836G>T) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about ADGRE3 p.Trp612Cys (c.1836G>T)?

AlphaMissense predicts likely benign (score 0.3283) — an in-silico prediction, not a clinical call.

ADGRE3 p.Trp612Cys

c.1836G>T · rs751299196 · VCV2291154

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3283 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3283	likely benign
REVEL	0.268	benign-leaning
SaProt	LLR -9.26	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 6.1	GERP 1.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 55 kb · p 0.027 · regional, not allelic
Overall
CADD	23.1	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 0.00669% East Asian · 3/44,858 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.000205% 3/1,460,940 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: ADGRE3
Protein: p.Trp612Cys
Coding: c.1836G>T
MANE Select: NM_032571
dbSNP: rs751299196
Type: single nucleotide variant
Location: chr19:14625576 (GRCh38)
Gene constraint: LOEUF 1.265 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.74

Full ADGRE3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADGRE3 p.Ala198Glu Uncertain significance ★ ⚠ same type
ADGRE3 p.Ala198Ser Uncertain significance ★ ⚠ same type
ADGRE3 p.Ala342Thr Uncertain significance ★ ⚠ same type
ADGRE3 p.Ala374Val Uncertain significance ★ ⚠ same type
ADGRE3 p.Asn39Ser Uncertain significance ★ ⚠ same type
ADGRE3 p.Asn450Asp Uncertain significance ★ ⚠ same type
ADGRE3 p.Asn538Ser Uncertain significance ★ ⚠ same type
ADGRE3 p.Asn66Asp 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/adgre3-p-trp612cys (accessed [today's date]).

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