# NM_207122.2(EXT2):c.590del (p.Pro197fs)

https://sugi.bio/variant/ext2-p-pro197fs

## Summary

**EXT2 p.Pro197fs (c.590del)** is classified **Pathogenic** in EXT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-03-11). No gnomAD frequency available for this variant; Associated with exostoses, multiple, type 2.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1565197245 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the EXT2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to exostoses, multiple, type 2.

*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 dominant |
| Age of onset (of this condition) | Childhood |
| Prevalence | >1 / 1000 (Specific population) |
| Diagnostic panels | EXT2 is a diagnostic-grade gene on 16 Genomics England panels |

**Commonly reported features of Multiple osteochondromas** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Osteochondroma — Obligate (100%)
- Limitation of joint mobility — Frequent (79-30%)
- Abnormal cartilage morphology — Frequent (79-30%)
- Abnormality of the knee — Frequent (79-30%)
- Abnormality of femur morphology — Frequent (79-30%)
- Abnormal bone structure — Frequent (79-30%)
- Deformed forearm bones — Frequent (79-30%)
- Functional motor deficit — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002205/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EXT2](https://sugi.bio/atlas/gene/EXT2/) |
| Protein change (HGVS p.) | p.Pro197fs |
| Coding change (HGVS c.) | c.590del |
| MANE Select transcript | [NM_207122](https://www.ncbi.nlm.nih.gov/nuccore/NM_207122) |
| dbSNP | [rs1565197245](https://www.ncbi.nlm.nih.gov/snp/rs1565197245/) |
| Variant type | Deletion |
| Location | chr11:44109243-44109243 (GRCh38) |
| ClinVar | [VCV657872](https://www.ncbi.nlm.nih.gov/clinvar/variation/657872/) |

**All HGVS expressions:** `LRG_494:g.18699del`, `LRG_494t1:c.689del`, `LRG_494t2:c.590del`, `NC_000011.10:g.44109247del`, `NC_000011.9:g.44130797del`, `NG_007560.1:g.18699del`, `NM_000401.3:c.689del`, `NM_001178083.3:c.590del`, `NM_001389628.1:c.590del`, `NM_001389630.1:c.590del`, `NM_207122.1:c.590delC`, `NM_207122.2:c.590del`

## 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 -3.691, GERP -5.49 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 14**, 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}

**EXT2** population constraint: LOEUF 0.775, pLI 1.2232e-10, missense-Z 2.1935; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **exostoses, multiple, type 2** — Definitive (AD)

## Protein context {#protein}

Residue **197** lies in a turn.

AlphaFold model confidence (whole protein): pLDDT 87.59, 67% of residues very-high.

**6 experimental structure(s)** (PDB): [7SCH](https://www.rcsb.org/structure/7SCH), [7SCJ](https://www.rcsb.org/structure/7SCJ), [7SCK](https://www.rcsb.org/structure/7SCK), [7UQX](https://www.rcsb.org/structure/7UQX), [7UQY](https://www.rcsb.org/structure/7UQY), [7ZAY](https://www.rcsb.org/structure/7ZAY).

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

*Describes the biological roles of EXT2 (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:** EXT2's established molecular role includes glucuronosyltransferase activity. In Reactome, EXT2 is annotated in disease pathway(s) including **Defective EXT1 causes exostoses 1, TRPS2 and CHDS**, **Defective EXT2 causes exostoses 2**.

**Disease mechanism (Reactome):** EXT2 loss or alteration is curated in [Defective EXT1 causes exostoses 1, TRPS2 and CHDS](https://reactome.org/content/detail/R-HSA-3656253), [Defective EXT2 causes exostoses 2](https://reactome.org/content/detail/R-HSA-3656237).

### Pathways affected {#pathways}

EXT2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective EXT1 causes exostoses 1, TRPS2 and CHDS](https://reactome.org/content/detail/R-HSA-3656253) | curated |
| ⚕ [Defective EXT2 causes exostoses 2](https://reactome.org/content/detail/R-HSA-3656237) | curated |
| [HS-GAG biosynthesis](https://reactome.org/content/detail/R-HSA-2022928) | curated |

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

**Molecular function:** glucuronosyltransferase activity, glycosyltransferase activity, protein heterodimerization activity, glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity.

**Biological process:** polysaccharide biosynthetic process, ossification, glycosaminoglycan biosynthetic process, heparan sulfate proteoglycan biosynthetic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-03-11.

**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 | 2019-03-11 |

## Associated conditions {#conditions}

[exostoses, multiple, type 2](https://sugi.bio/atlas/disease/exostoses-multiple-type-2/).

**Reported phenotype names (ClinVar):** Exostoses, multiple, type 2, Hereditary Multiple Osteochondromatosis, Type II, EXOSTOSES, MULTIPLE, TYPE II.

## Similar variants {#similar}

Related EXT2 variant pages (same residue, condition, or type): [EXT2 c.626+2_626+5del](/variant/ext2-c-626-plus-2-626-plus-5del), [EXT2 p.Gln382fs](/variant/ext2-p-gln382fs), [EXT2 p.Val593fs](/variant/ext2-p-val593fs), [EXT2 p.Val68fs](/variant/ext2-p-val68fs), [EXT2 c.2019-2del](/variant/ext2-c-2019-minus-2del), [EXT2 c.1806+9del](/variant/ext2-c-1806-plus-9del), [EXT2 c.1080-2del](/variant/ext2-c-1080-minus-2del), [EXT2 c.1489_1495+12del](/variant/ext2-c-1489-1495-plus-12del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 657872). 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.*