Is ADGRE2 p.Arg472Cys (c.1414C>T) pathogenic?

ADGRE2 p.Arg472Cys (c.1414C>T) is classified Uncertain significance in ADGRE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-11). AlphaMissense: likely benign (0.1109); Ultra-rare (popmax 0.0461%, sas).

How common is ADGRE2 p.Arg472Cys (c.1414C>T) in the general population?

ADGRE2 p.Arg472Cys (c.1414C>T) is ultra-rare (popmax 0.0461%, sas) (gnomAD).

What do computational predictors say about ADGRE2 p.Arg472Cys (c.1414C>T)?

AlphaMissense predicts likely benign (score 0.1109) — an in-silico prediction, not a clinical call.

ADGRE2 p.Arg472Cys

c.1414C>T · rs561706740 · VCV2902081

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1109 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0461%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1109	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR -10.32	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.60 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.051	GERP -0.75
Regional constraint	o/e 0.82	unconstrained · MANE · 29 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	17.53	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 0.0461% South Asian · 42/91,064 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0311%

Overall 0.00502% 81/1,613,758 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0461%	2,168
Remaining individualsnot grpmax-eligible	0.0064%	15,622
European (non-Finnish)	0.00288%	34,696
African / African-American	0.00133%	75,026

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.Arg472Cys
Coding: c.1414C>T
MANE Select: NM_013447
dbSNP: rs561706740
Type: single nucleotide variant
Location: chr19:14755656 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.44 · 3 PDB
Residue 472: the gain-b domain

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

Similar variants

ADGRE2 p.Arg472His Uncertain significance ★ ⚠ same residue
ADGRE2 p.Arg472Pro Uncertain significance ★ ⚠ same residue
ADGRE2 p.Ala359Gly Uncertain significance ★★ ⚠ same type
ADGRE2 p.Ala44Thr Uncertain significance ★★ ⚠ same type
ADGRE2 p.Ala554Val Uncertain significance ★★ ⚠ same type
ADGRE2 p.Ala555Ser Uncertain significance ★★ ⚠ same type
ADGRE2 p.Ala589Thr Uncertain significance ★★ ⚠ same type
ADGRE2 p.Ala603Thr 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/adgre2-p-arg472cys (accessed [today's date]).

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