# NM_000127.3(EXT1):c.1298_1299del (p.Arg433fs)

https://sugi.bio/variant/ext1-p-arg433fs

## Summary

**EXT1 p.Arg433fs (c.1298_1299del)** is classified **Pathogenic** in EXT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-10).

**At a glance:** Pathogenic · review: Single submitter · 1 submitter

## For patients & families {#patients}

This is a change in the EXT1 gene that is reported as disease-causing, but on limited review, 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 | [EXT1](https://sugi.bio/atlas/gene/EXT1/) |
| Protein change (HGVS p.) | p.Arg433fs |
| Coding change (HGVS c.) | c.1298_1299del |
| MANE Select transcript | [NM_000127](https://www.ncbi.nlm.nih.gov/nuccore/NM_000127) |
| Variant type | Deletion |
| Location | chr8:117822583-117822584 (GRCh38) |
| ClinVar | [VCV3340270](https://www.ncbi.nlm.nih.gov/clinvar/variation/3340270/) |

**All HGVS expressions:** `LRG_493:g.294236_294237del`, `LRG_493t1:c.1298_1299del`, `NC_000008.10:g.118834823_118834824del`, `NC_000008.11:g.117822584_117822585del`, `NG_007455.2:g.294236_294237del`, `NM_000127.2:c.1297_1298delAG`, `NM_000127.3:c.1298_1299del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.906, GERP 1.67, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.339, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 5 of 11**, 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.

*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}

**EXT1** population constraint: LOEUF 0.339, pLI 1, missense-Z 2.7372; 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 1** — Definitive (AD)

## Protein context {#protein}

Residue **433** lies in a turn.

AlphaFold model confidence (whole protein): pLDDT 84.67, 66% 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 EXT1 (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:** EXT1's established molecular role includes protein homodimerization activity. In Reactome, EXT1 is annotated in disease pathway(s) including **Defective EXT1 causes exostoses 1, TRPS2 and CHDS**, **Defective EXT2 causes exostoses 2**.

**Disease mechanism (Reactome):** EXT1 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}

EXT1 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:** protein homodimerization activity, protein heterodimerization activity, glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity, N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase 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 2023-07-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2023-07-10 |

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

## Similar variants {#similar}

Related EXT1 variant pages (same residue, condition, or type): [EXT1 p.Arg433Gly](/variant/ext1-p-arg433gly), [EXT1 p.Arg433=](/variant/ext1-p-arg433), [EXT1 p.Ala594fs](/variant/ext1-p-ala594fs), [EXT1 p.Ala693fs](/variant/ext1-p-ala693fs), [EXT1 p.Arg405fs](/variant/ext1-p-arg405fs), [EXT1 p.Gln508fs](/variant/ext1-p-gln508fs), [EXT1 p.Glu39fs](/variant/ext1-p-glu39fs), [EXT1 p.Leu490fs](/variant/ext1-p-leu490fs).

### 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 3340270). 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.*