# NM_014244.5(ADAMTS2):c.274del (p.Val92fs)

https://sugi.bio/variant/adamts2-p-val92fs

## Summary

**ADAMTS2 p.Val92fs (c.274del)** is classified **Pathogenic** in ADAMTS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-31). No gnomAD frequency available for this variant; Associated with Ehlers-Danlos syndrome, dermatosparaxis type.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2127463432 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ADAMTS2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Ehlers-Danlos syndrome, dermatosparaxis type.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | ADAMTS2 is a diagnostic-grade gene on 1 Genomics England panel |

**Commonly reported features of Dermatosparaxis Ehlers-Danlos syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Osteopenia — Very frequent (99-80%)
- Osteoporosis — Very frequent (99-80%)
- Thin skin — Very frequent (99-80%)
- Hyperextensible skin — Very frequent (99-80%)
- Abnormality of subcutaneous fat tissue — Very frequent (99-80%)
- Hypotonia — Very frequent (99-80%)
- Abnormal joint morphology — Very frequent (99-80%)
- Joint dislocation — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002089/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ADAMTS2](https://sugi.bio/atlas/gene/ADAMTS2/) |
| Protein change (HGVS p.) | p.Val92fs |
| Coding change (HGVS c.) | c.274del |
| MANE Select transcript | [NM_014244](https://www.ncbi.nlm.nih.gov/nuccore/NM_014244) |
| dbSNP | [rs2127463432](https://www.ncbi.nlm.nih.gov/snp/rs2127463432/) |
| Variant type | Deletion |
| Location | chr5:179344027-179344027 (GRCh38) |
| ClinVar | [VCV1453000](https://www.ncbi.nlm.nih.gov/clinvar/variation/1453000/) |

**All HGVS expressions:** `NC_000005.10:g.179344028del`, `NC_000005.9:g.178771029del`, `NG_023212.3:g.6302del`, `NM_014244.5:c.274del`, `NM_021599.4:c.274del`

## 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 -0.281, GERP -3.08 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.568, pLI 0.0010101. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 22**, so the transcript is predicted to undergo NMD.
- 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: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**ADAMTS2** population constraint: LOEUF 0.568, pLI 0.0010101, missense-Z 1.4864; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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 71.59, 15% of residues very-high.

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

*Describes the biological roles of ADAMTS2 (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:** ADAMTS2 participates in disease-associated pathways. In Reactome, ADAMTS2 is annotated in disease pathway(s) including **Defective B3GALTL causes PpS**.

**Disease mechanism (Reactome):** ADAMTS2 loss or alteration is curated in [Defective B3GALTL causes PpS](https://reactome.org/content/detail/R-HSA-5083635).

### Pathways affected {#pathways}

ADAMTS2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective B3GALTL causes PpS](https://reactome.org/content/detail/R-HSA-5083635) | curated |
| [Collagen biosynthesis and modifying enzymes](https://reactome.org/content/detail/R-HSA-1650814) | curated |
| [O-glycosylation of TSR domain-containing proteins](https://reactome.org/content/detail/R-HSA-5173214) | curated |

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-07-31.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2021-07-31 |

## Associated conditions {#conditions}

[Ehlers-Danlos syndrome, dermatosparaxis type](https://sugi.bio/atlas/disease/ehlers-danlos-syndrome-dermatosparaxis-type/).

**Reported phenotype names (ClinVar):** Ehlers-Danlos syndrome, dermatosparaxis type, EDS VIIC, Dermatosparaxis, Ehlers-Danlos syndrome, type VII, autosomal recessive.

## Similar variants {#similar}

Related ADAMTS2 variant pages (same residue, condition, or type): [ADAMTS2 c.689-9_695del](/variant/adamts2-c-689-minus-9-695del), [ADAMTS2 p.Ala89fs](/variant/adamts2-p-ala89fs), [ADAMTS2 p.Met791fs](/variant/adamts2-p-met791fs), [ADAMTS2 p.Pro33fs](/variant/adamts2-p-pro33fs), [ADAMTS2 p.Pro34fs](/variant/adamts2-p-pro34fs), [ADAMTS2 p.Pro46fs](/variant/adamts2-p-pro46fs), [ADAMTS2 p.Tyr834_Met835insTer](/variant/adamts2-p-tyr834-met835inster), [ADAMTS2 p.22_26LLPPP[1]](/variant/adamts2-p-22-26llppp-1).

### 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 1453000). 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.*