Is ADGRB2 p.Pro451Ser (c.1351C>T) pathogenic?

ADGRB2 p.Pro451Ser (c.1351C>T) is classified Uncertain significance in ADGRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-05). AlphaMissense: likely benign (0.0872); Ultra-rare (popmax 0.0381%, nfe).

How common is ADGRB2 p.Pro451Ser (c.1351C>T) in the general population?

ADGRB2 p.Pro451Ser (c.1351C>T) is ultra-rare (popmax 0.0381%, nfe) (gnomAD).

What do computational predictors say about ADGRB2 p.Pro451Ser (c.1351C>T)?

AlphaMissense predicts likely benign (score 0.0872) — an in-silico prediction, not a clinical call.

ADGRB2 p.Pro451Ser

c.1351C>T · rs139751061 · VCV2180247

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0872 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0381%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0872	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -6.23	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 12	GERP 1.1, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 17 kb · p 5.9e-11 · regional, not allelic
Overall
CADD	21.5	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 0.0381% European (non-Finnish) · 450/1,179,896 alleles

Filtering AF 0.0352% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.034%

Overall 0.0293% 473/1,613,148 alleles · ultra-rare exomes 430/1,460,958 · genomes 43/152,190 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0381%	2,622
Remaining individualsnot grpmax-eligible	0.0176%	5,679
African / African-American	0.0133%	7,493
Finnishnot grpmax-eligible	0.00316%	31,692

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.Pro451Ser
Coding: c.1351C>T
MANE Select: NM_001364857
dbSNP: rs139751061
Type: single nucleotide variant
Location: chr1:31742119 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.10 · 1 PDB
Residue 451: the tsp type-1 3 domain

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

Similar variants

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
ADGRB2 p.Arg1105Cys 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-pro451ser (accessed [today's date]).

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