# NM_001364857.2(ADGRB2):c.267G>A (p.Val89=)

https://sugi.bio/variant/adgrb2-p-val89

## Summary

**ADGRB2 p.Val89= (c.267G>A)** is classified **Uncertain significance** in ADGRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-12). Very rare (popmax 0.00458%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1330388021 · 1 submitter · very rare (popmax 0.00458%, nfe)

## For patients & families {#patients}

This is a change in the ADGRB2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ADGRB2](https://sugi.bio/atlas/gene/ADGRB2/) |
| Protein change (HGVS p.) | p.Val89= |
| Coding change (HGVS c.) | c.267G>A |
| MANE Select transcript | [NM_001364857](https://www.ncbi.nlm.nih.gov/nuccore/NM_001364857) |
| dbSNP | [rs1330388021](https://www.ncbi.nlm.nih.gov/snp/rs1330388021/) |
| Variant type | single nucleotide variant |
| Location | chr1:31756570-31756570 (GRCh38) |
| ClinVar | [VCV2982967](https://www.ncbi.nlm.nih.gov/clinvar/variation/2982967/) |

**All HGVS expressions:** `NC_000001.10:g.32222171C>T`, `NC_000001.11:g.31756570C>T`, `NG_090409.1:g.686C>T`, `NG_090410.1:g.80C>T`, `NM_001294335.2:c.267G>A`, `NM_001294336.2:c.267G>A`, `NM_001364857.2:c.267G>A`, `NM_001703.2:c.267G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.47) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.945, GERP 1.78, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 18.83**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.47**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.47**.
- Pangolin: Δ**0.35** (gain), gain 0.35 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00458%** (nfe) · FAF95 0.00359% · FAF99 0.00321% · 54/1,178,764 in the highest group · 54/1,611,856 alleles overall — very rare (popmax 0.00458%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ADGRB2** population constraint: LOEUF 0.383, pLI 1, missense-Z 3.8435. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 62.10, 13% of residues very-high.

**1 experimental structure(s)** (PDB): [8OEK](https://www.rcsb.org/structure/8OEK).

## What this gene does {#gene-function}

*Describes the biological roles of ADGRB2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ADGRB2's established molecular role includes G protein-coupled receptor activity.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** G protein-coupled receptor activity.

**Biological process:** G protein-coupled receptor signaling pathway, calcineurin-NFAT signaling cascade.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-12.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-10-12 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ADGRB2 variant pages (same residue, condition, or type): [ADGRB2 p.Ala117Val](/variant/adgrb2-p-ala117val), [ADGRB2 p.Ala1193Thr](/variant/adgrb2-p-ala1193thr), [ADGRB2 p.Ala1193Val](/variant/adgrb2-p-ala1193val), [ADGRB2 p.Ala1411Val](/variant/adgrb2-p-ala1411val), [ADGRB2 p.Ala36Thr](/variant/adgrb2-p-ala36thr), [ADGRB2 p.Ala733Thr](/variant/adgrb2-p-ala733thr), [ADGRB2 p.Ala901Thr](/variant/adgrb2-p-ala901thr), [ADGRB2 p.Arg1105Cys](/variant/adgrb2-p-arg1105cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2982967). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*