# NM_000127.3(EXT1):c.1263G>A (p.Lys421=)

https://sugi.bio/variant/ext1-p-lys421

## Summary

**EXT1 p.Lys421= (c.1263G>A)** is classified **Likely benign** in EXT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-22). Very rare (popmax 0.00178%, nfe); Associated with hereditary multiple osteochondromas.

**At a glance:** Likely benign · review: Single submitter · rsID rs2129772013 · 1 submitter · 1 linked condition · very rare (popmax 0.00178%, nfe)

## For patients & families {#patients}

This is a change in the EXT1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to hereditary multiple osteochondromas.

*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) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | EXT1 is a diagnostic-grade gene on 14 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/0007035/index) · [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.Lys421= |
| Coding change (HGVS c.) | c.1263G>A |
| MANE Select transcript | [NM_000127](https://www.ncbi.nlm.nih.gov/nuccore/NM_000127) |
| dbSNP | [rs2129772013](https://www.ncbi.nlm.nih.gov/snp/rs2129772013/) |
| Variant type | single nucleotide variant |
| Location | chr8:117830251-117830251 (GRCh38) |
| ClinVar | [VCV1597285](https://www.ncbi.nlm.nih.gov/clinvar/variation/1597285/) |

**All HGVS expressions:** `LRG_493:g.286569G>A`, `NC_000008.10:g.118842490C>T`, `NC_000008.11:g.117830251C>T`, `NG_007455.2:g.286569G>A`, `NM_000127.3:c.1263G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.48) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 7.669, GERP 1.83, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 14.77**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.48**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 21 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00178%** (nfe) · FAF95 0.00114% · FAF99 0.000971% · 21/1,179,994 in the highest group · 23/1,614,024 alleles overall — very rare (popmax 0.00178%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,251 |
| European (non-Finnish) (grpmax) | 0.00178% | 56,190 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **421** lies in an α-helix.

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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-07-22.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-07-22 |

## Associated conditions {#conditions}

[hereditary multiple osteochondromas](https://sugi.bio/atlas/disease/hereditary-multiple-osteochondromas/).

**Reported phenotype names (ClinVar):** Multiple congenital exostosis, MULTIPLE CARTILAGINOUS EXOSTOSES, Multiple osteochondromas, Hereditary multiple osteochondromas, Hereditary multiple exostoses, Hereditary multiple exostosis, Multiple exostoses.

## Similar variants {#similar}

Related EXT1 variant pages (same residue, condition, or type): [EXT1 p.Lys421Glu](/variant/ext1-p-lys421glu), [EXT1 c.1056+1G>A](/variant/ext1-c-1056-plus-1g-a), [EXT1 c.1056+1G>T](/variant/ext1-c-1056-plus-1g-t), [EXT1 c.1165-1G>A](/variant/ext1-c-1165-minus-1g-a), [EXT1 c.1285-1G>C](/variant/ext1-c-1285-minus-1g-c), [EXT1 c.1417+1G>A](/variant/ext1-c-1417-plus-1g-a), [EXT1 c.1417+1G>T](/variant/ext1-c-1417-plus-1g-t), [EXT1 c.1418-1G>A](/variant/ext1-c-1418-minus-1g-a).

### 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 1597285). 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.*