# NM_207122.2(EXT2):c.1393C>T (p.Arg465Ter)

https://sugi.bio/variant/ext2-p-arg465ter

## Summary

**EXT2 p.Arg465Ter (c.1393C>T)** is classified **Conflicting classifications of pathogenicity** in EXT2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-09-10). Ultra-rare (popmax 0.0165%, mid); Associated with exostoses, multiple, type 2.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs772690312 · 8 submitters · 2 linked conditions · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the EXT2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 8 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.Arg465Ter |
| Coding change (HGVS c.) | c.1393C>T |
| MANE Select transcript | [NM_207122](https://www.ncbi.nlm.nih.gov/nuccore/NM_207122) |
| dbSNP | [rs772690312](https://www.ncbi.nlm.nih.gov/snp/rs772690312/) |
| Variant type | single nucleotide variant |
| Location | chr11:44197916-44197916 (GRCh38) |
| ClinVar | [VCV580003](https://www.ncbi.nlm.nih.gov/clinvar/variation/580003/) |

**All HGVS expressions:** `LRG_494:g.107368C>T`, `LRG_494t1:c.1492C>T`, `LRG_494t2:c.1393C>T`, `NC_000011.10:g.44197916C>T`, `NC_000011.9:g.44219466C>T`, `NG_007560.1:g.107368C>T`, `NM_000401.3:c.1492C>T`, `NM_001178083.3:c.1423C>T`, `NM_001389628.1:c.1393C>T`, `NM_001389630.1:c.1393C>T`, `NM_207122.2:c.1393C>T`

## 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 1.387, GERP -0.303, phastCons 1 — weakly conserved position
- Molecular consequence: **nonsense (stop-gain)** — 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 9 of 14**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 37.0**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for EXT2 (904 scored positions, the nearest 36 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.00255% · FAF99 0.00161% · 1/6,060 in the highest group · 23/1,614,068 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,060 |
| African / African-American | 0.00666% | 15,007 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,252 |
| East Asian | 0.00223% | 44,876 |
| Admixed American | 0.00167% | 60,018 |
| South Asian | 0.0011% | 91,084 |
| European (non-Finnish) | 0.00102% | 98,329 |

*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 **465** lies in a binding site.

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-09-10.

**Submitter consensus:** conflicting (4 Pathogenic, 3 Uncertain significance, 1 Likely pathogenic).

**Submission history:** 8 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2018-10-31 |
| Genomic Research Center, Shahid Beheshti University of Medical Sciences | Pathogenic | criteria provided, single submitter | clinical testing | 2020-05-03 |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-09-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-21 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2022-03-31 |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-12-20 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-10 |
| Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-05-09 |

## 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, not provided, none provided, EXOSTOSES, MULTIPLE, TYPE II, Hereditary Multiple Osteochondromatosis, Type II, SEIZURES, SCOLIOSIS, AND MACROCEPHALY/MICROCEPHALY SYNDROME, Seizures, scoliosis, and macrocephaly syndrome.

## Similar variants {#similar}

Related EXT2 variant pages (same residue, condition, or type): [EXT2 p.Arg465Gln](/variant/ext2-p-arg465gln), [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 2026-10-15); 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 580003). 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.*