Is ADGRA2 p.Arg652Cys (c.1954C>T) pathogenic?

ADGRA2 p.Arg652Cys (c.1954C>T) is classified Uncertain significance in ADGRA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-13). AlphaMissense: likely benign (0.2772); Ultra-rare (popmax 0.0217%, nfe).

How common is ADGRA2 p.Arg652Cys (c.1954C>T) in the general population?

ADGRA2 p.Arg652Cys (c.1954C>T) is ultra-rare (popmax 0.0217%, nfe) (gnomAD).

What do computational predictors say about ADGRA2 p.Arg652Cys (c.1954C>T)?

AlphaMissense predicts likely benign (score 0.2772) — an in-silico prediction, not a clinical call.

ADGRA2 p.Arg652Cys

c.1954C>T · rs763915452 · VCV2356578

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2772 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2772	likely benign
REVEL	0.298	indeterminate
SaProt	LLR -10.24	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 45 kb · p 0.0006 · regional, not allelic
Overall
CADD	32.0	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 0.0217% European (non-Finnish) · 256/1,179,948 alleles

Filtering AF 0.0195% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0186%

Overall 0.0177% 286/1,613,784 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0217%	4,609
African / African-American	0.016%	6,242
Remaining individualsnot grpmax-eligible	0.016%	6,248
Admixed American	0.01%	10,001
East Asian	0.00223%	44,892
South Asian	0.0011%	91,092

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: ADGRA2
Protein: p.Arg652Cys
Coding: c.1954C>T
MANE Select: NM_032777
dbSNP: rs763915452
Type: single nucleotide variant
Location: chr8:37835674 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.47
Residue 652: the gain-b domain

Full ADGRA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADGRA2 c.1608+5T>C Benign ★★ same type
ADGRA2 p.Ala681Thr Benign ★★ ⚠ same type
ADGRA2 p.Arg671= Benign ★★ same type
ADGRA2 p.Ala1082Ser Uncertain significance ★ ⚠ same type
ADGRA2 p.Ala1094Ser Uncertain significance ★ ⚠ same type
ADGRA2 p.Ala1098Val Uncertain significance ★ ⚠ same type
ADGRA2 p.Ala1102Thr Uncertain significance ★ ⚠ same type
ADGRA2 p.Ala1102Val 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/adgra2-p-arg652cys (accessed [today's date]).

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