Is ADGRB2 p.Pro340Arg (c.1019C>G) pathogenic?

ADGRB2 p.Pro340Arg (c.1019C>G) is classified Uncertain significance in ADGRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-26). AlphaMissense: likely pathogenic (0.8514); Very rare (popmax 0.00733%, eas).

How common is ADGRB2 p.Pro340Arg (c.1019C>G) in the general population?

ADGRB2 p.Pro340Arg (c.1019C>G) is very rare (popmax 0.00733%, eas) (gnomAD).

What do computational predictors say about ADGRB2 p.Pro340Arg (c.1019C>G)?

AlphaMissense predicts likely pathogenic (score 0.8514) — an in-silico prediction, not a clinical call.

ADGRB2 p.Pro340Arg

c.1019C>G · rs146816893 · VCV3084007

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8514 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00733%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8514	likely pathogenic
REVEL	0.392	indeterminate
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 17 kb · p 5.9e-11 · regional, not allelic
Overall
CADD	29.7	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 0.00733% East Asian · 3/40,914 alleles

Filtering AF 0.00194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00135% 21/1,551,098 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00733%	13,638
Admixed American	0.00393%	25,431
Remaining individualsnot grpmax-eligible	0.00333%	30,038
African / African-American	0.00137%	73,012
South Asian	0.00119%	84,038
European (non-Finnish)	0.00105%	95,568

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: ADGRB2
Protein: p.Pro340Arg
Coding: c.1019C>G
MANE Select: NM_001364857
dbSNP: rs146816893
Type: single nucleotide variant
Location: chr1:31744261 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.10 · 1 PDB
Residue 340: the tsp type-1 1 domain; a disulfide bond

Full ADGRB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADGRB2 p.Pro340His Uncertain significance ★ ⚠ same residue
ADGRB2 p.Pro340Leu Uncertain significance ★ ⚠ same residue
ADGRB2 p.Pro340= Likely benign ★ same residue
ADGRB2 p.Ala117Val Uncertain significance ★★ ⚠ same type
ADGRB2 p.Ala1193Thr Uncertain significance ★★ ⚠ same type
ADGRB2 p.Ala1193Val Uncertain significance ★★ ⚠ same type
ADGRB2 p.Ala1411Val Uncertain significance ★★ ⚠ same type
ADGRB2 p.Ala36Thr 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/adgrb2-p-pro340arg (accessed [today's date]).

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