# NM_207122.2(EXT2):c.1771T>C (p.Ser591Pro)

https://sugi.bio/variant/ext2-p-ser591pro

## Summary

**EXT2 p.Ser591Pro (c.1771T>C)** is classified **Uncertain significance** in EXT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-27). AlphaMissense: likely pathogenic (0.9995); Very rare (popmax 0.00237%, nfe); Associated with exostoses, multiple, type 2.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs370187162 · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00237%, nfe)

## For patients & families {#patients}

This is a change in the EXT2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, 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.Ser591Pro |
| Coding change (HGVS c.) | c.1771T>C |
| MANE Select transcript | [NM_207122](https://www.ncbi.nlm.nih.gov/nuccore/NM_207122) |
| dbSNP | [rs370187162](https://www.ncbi.nlm.nih.gov/snp/rs370187162/) |
| Variant type | single nucleotide variant |
| Location | chr11:44232461-44232461 (GRCh38) |
| ClinVar | [VCV2065035](https://www.ncbi.nlm.nih.gov/clinvar/variation/2065035/) |

**All HGVS expressions:** `LRG_494:g.141913T>C`, `LRG_494t1:c.1870T>C`, `LRG_494t2:c.1771T>C`, `NC_000011.10:g.44232461T>C`, `NC_000011.9:g.44254011T>C`, `NG_007560.1:g.141913T>C`, `NM_000401.3:c.1870T>C`, `NM_001178083.3:c.1801T>C`, `NM_001389628.1:c.1771T>C`, `NM_001389630.1:c.1771T>C`, `NM_207122.2:c.1771T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9995)
- REVEL 0.965 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.554 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.846, GERP 2.2, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 2%** most-pathogenic-predicted substitutions in EXT2 (of 4,253 modeled).
- CADD: **PHRED 29.2**. 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.*
- Regional missense constraint: **o/e 0.62** across the covering region of the MANE Select transcript (44,206,880–44,244,284), spanning 37,404 bp. Chi-square p 3.2e-09. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00237%** (nfe) · FAF95 0.00164% · FAF99 0.00142% · 28/1,179,960 in the highest group · 30/1,613,894 alleles overall — very rare (popmax 0.00237%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00237% | 42,141 |
| African / African-American | 0.00134% | 74,894 |
| South Asian | 0.0011% | 91,070 |

*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}


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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-02-27.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-07-14 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-27 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Exostoses, multiple, type 2, Seizures-scoliosis-macrocephaly syndrome, EXOSTOSES, MULTIPLE, TYPE II, Hereditary Multiple Osteochondromatosis, Type II, Seizures, scoliosis, and macrocephaly syndrome, SEIZURES, SCOLIOSIS, AND MACROCEPHALY/MICROCEPHALY SYNDROME.

## Similar variants {#similar}

Related EXT2 variant pages (same residue, condition, or type): [EXT2 p.Ser591=](/variant/ext2-p-ser591), [EXT2 c.1079+1G>A](/variant/ext2-c-1079-plus-1g-a), [EXT2 c.1079+1G>T](/variant/ext2-c-1079-plus-1g-t), [EXT2 c.1173+1G>A](/variant/ext2-c-1173-plus-1g-a), [EXT2 c.1662+1G>C](/variant/ext2-c-1662-plus-1g-c), [EXT2 c.536+1G>A](/variant/ext2-c-536-plus-1g-a), [EXT2 c.626+1G>A](/variant/ext2-c-626-plus-1g-a), [EXT2 c.626+1G>C](/variant/ext2-c-626-plus-1g-c).

### 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 2065035). 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.*