# NM_013447.4(ADGRE2):c.2063del (p.Phe688fs)

https://sugi.bio/variant/adgre2-p-phe688fs

## Summary

**ADGRE2 p.Phe688fs (c.2063del)** is classified **Uncertain significance** in ADGRE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-18). Very rare (popmax 0.00134%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1180038250 · 1 submitter · very rare (popmax 0.00134%, afr)

## For patients & families {#patients}

This is a change in the ADGRE2 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 | [ADGRE2](https://sugi.bio/atlas/gene/ADGRE2/) |
| Protein change (HGVS p.) | p.Phe688fs |
| Coding change (HGVS c.) | c.2063del |
| MANE Select transcript | [NM_013447](https://www.ncbi.nlm.nih.gov/nuccore/NM_013447) |
| dbSNP | [rs1180038250](https://www.ncbi.nlm.nih.gov/snp/rs1180038250/) |
| Variant type | Deletion |
| Location | chr19:14746924-14746924 (GRCh38) |
| ClinVar | [VCV3022634](https://www.ncbi.nlm.nih.gov/clinvar/variation/3022634/) |

**All HGVS expressions:** `NC_000019.10:g.14746925del`, `NC_000019.9:g.14857737del`, `NG_047146.1:g.36618del`, `NM_001271052.1:c.1889del`, `NM_013447.4:c.2063del`, `NM_152916.2:c.1916del`, `NM_152917.2:c.1784del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -3.79, GERP -1.75 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.028, pLI 3.7208e-23. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 17 of 21**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 27.3**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00134%** (afr) · 1/74,836 in the highest group · 1/151,954 alleles overall — very rare (popmax 0.00134%, afr).

*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}

**ADGRE2** population constraint: LOEUF 1.028, pLI 3.7208e-23, missense-Z 2.3707. *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 79.44, 17% of residues very-high.

**3 experimental structure(s)** (PDB): [2BO2](https://www.rcsb.org/structure/2BO2), [2BOU](https://www.rcsb.org/structure/2BOU), [2BOX](https://www.rcsb.org/structure/2BOX).

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

*Describes the biological roles of ADGRE2 (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:** ADGRE2's established molecular role includes chondroitin sulfate binding.


### Pathways affected {#pathways}

ADGRE2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Class B/2 (Secretin family receptors)](https://reactome.org/content/detail/R-HSA-373080) | curated |

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

**Molecular function:** chondroitin sulfate binding.

**Biological process:** cell adhesion, cell migration, regulation of mast cell degranulation, granulocyte chemotaxis.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-02-18.

**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 | 2023-02-18 |

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

## Similar variants {#similar}

Related ADGRE2 variant pages (same residue, condition, or type): [ADGRE2 c.1084+19_1084+36del](/variant/adgre2-c-1084-plus-19-1084-plus-36del), [ADGRE2 p.Gln565fs](/variant/adgre2-p-gln565fs), [ADGRE2 c.1085-3_1085-2del](/variant/adgre2-c-1085-minus-3-1085-minus-2del), [ADGRE2 c.2353-4_2354del](/variant/adgre2-c-2353-minus-4-2354del), [ADGRE2 c.355_355+7del](/variant/adgre2-c-355-355-plus-7del), [ADGRE2 p.Arg675fs](/variant/adgre2-p-arg675fs), [ADGRE2 p.Asn69del](/variant/adgre2-p-asn69del), [ADGRE2 p.Glu366del](/variant/adgre2-p-glu366del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 3022634). 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.*