Is ADGRB2 p.Pro1378= (c.4134G>C) pathogenic?

ADGRB2 p.Pro1378= (c.4134G>C) is classified Benign in ADGRB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-01). Common (popmax 67.1%, afr) — too common for a highly-penetrant pathogenic allele.

ADGRB2 p.Pro1378=

Q: How common is ADGRB2 p.Pro1378= (c.4134G>C) in the general population?

ADGRB2 p.Pro1378= (c.4134G>C) is common (popmax 67.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.4134G>C · rs909001 · VCV1596382

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 67.1%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.9	GERP -4.2
Overall
CADD	0.027	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 67.1% African / African-American · 49,886/74,300 alleles

Filtering AF 66.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 66.4%

Overall 21.6% 341,472/1,583,790 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	67.1%	1
South Asian	38.4%	3
Admixed American	26.5%	4
Finnishnot grpmax-eligible	22.8%	4
Remaining individualsnot grpmax-eligible	22.7%	4
East Asian	20.2%	5
European (non-Finnish)	17.2%	6
Middle Eastern	16.2%	6
Ashkenazi Jewishnot grpmax-eligible	16.1%	6
Amishnot grpmax-eligible	4.3%	23

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.Pro1378=
Coding: c.4134G>C
MANE Select: NM_001364857
dbSNP: rs909001
Type: single nucleotide variant
Location: chr1:31731046 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.10 · 1 PDB
Residue 1378: the 'disordered' region

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

Similar variants

ADGRB2 p.Pro1378Leu Uncertain significance ★ ⚠ 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
ADGRB2 p.Ala733Thr Uncertain significance ★★ ⚠ same type
ADGRB2 p.Ala901Thr 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-pro1378 (accessed [today's date]).

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