Is ADGRB1 p.Pro1295Ala (c.3883C>G) pathogenic?

ADGRB1 p.Pro1295Ala (c.3883C>G) is classified Uncertain significance in ADGRB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely benign (0.0615); Ultra-rare (popmax 0.0329%, mid).

How common is ADGRB1 p.Pro1295Ala (c.3883C>G) in the general population?

ADGRB1 p.Pro1295Ala (c.3883C>G) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about ADGRB1 p.Pro1295Ala (c.3883C>G)?

AlphaMissense predicts likely benign (score 0.0615) — an in-silico prediction, not a clinical call.

ADGRB1 p.Pro1295Ala

c.3883C>G · rs372148096 · VCV3083915

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0615 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0615	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -6.73	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 4.7	GERP -1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 2,272 bp · p 0.42 · regional, not allelic
Overall
CADD	10.79	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 0.0329% Middle Eastern · 2/6,082 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00583% 94/1,613,398 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,041
Remaining individualsnot grpmax-eligible	0.0176%	5,678
European (non-Finnish)	0.00644%	15,524
Admixed American	0.00333%	30,001
South Asian	0.00329%	30,363

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: ADGRB1
Protein: p.Pro1295Ala
Coding: c.3883C>G
MANE Select: NM_001702
dbSNP: rs372148096
Type: single nucleotide variant
Location: chr8:142542117 (GRCh38)
Gene constraint: LOEUF 0.372 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.83

Full ADGRB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADGRB1 p.Pro1295= Benign ★★ same residue
ADGRB1 c.2130+15C>G Benign ★★ same type
ADGRB1 p.Ala1507Val Benign ★★ same type
ADGRB1 p.Pro575= Benign ★★ same type
ADGRB1 p.Ser480= Benign ★★ same type
ADGRB1 p.Thr1274= Benign ★★ same type
ADGRB1 p.Ala131Thr Uncertain significance ★ ⚠ same type
ADGRB1 p.Ala1406Gly 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/adgrb1-p-pro1295ala (accessed [today's date]).

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