# NM_001369268.1(ACAN):c.2112dup (p.Val705fs)

https://sugi.bio/variant/acan-p-val705fs

## Summary

**ACAN p.Val705fs (c.2112dup)** is classified **Pathogenic** in ACAN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-24). Associated with short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans.

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

## For patients & families {#patients}

This is a change in the ACAN gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans.

*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 |
| Diagnostic panels | ACAN is a diagnostic-grade gene on 5 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004133/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACAN](https://sugi.bio/atlas/gene/ACAN/) |
| Protein change (HGVS p.) | p.Val705fs |
| Coding change (HGVS c.) | c.2112dup |
| MANE Select transcript | [NM_001369268](https://www.ncbi.nlm.nih.gov/nuccore/NM_001369268) |
| Variant type | Duplication |
| Location | chr15:88851877-88851878 (GRCh38) |
| ClinVar | [VCV3342274](https://www.ncbi.nlm.nih.gov/clinvar/variation/3342274/) |

**All HGVS expressions:** `NC_000015.10:g.88851879dup`, `NC_000015.9:g.89395110dup`, `NG_012794.1:g.53437dup`, `NM_001135.4:c.2112dup`, `NM_001369268.1:c.2112dup`, `NM_001411096.1:c.2112dup`, `NM_001411097.1:c.2112dup`, `NM_013227.4:c.2112dup`

## 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 1.074, GERP 1.58 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.377, 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 11 of 19**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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}

**ACAN** population constraint: LOEUF 0.377, pLI 1, missense-Z 0.32052. *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):

- **ACAN-related short stature spectrum** — Definitive (AD)

## Protein context {#protein}

Residue **705** lies in the 'ks' region.

AlphaFold model confidence (whole protein): pLDDT 53.32, 17% of residues very-high.

**4 experimental structure(s)** (PDB): [4MD4](https://www.rcsb.org/structure/4MD4), [7RDV](https://www.rcsb.org/structure/7RDV), [9DFF](https://www.rcsb.org/structure/9DFF), [9DFT](https://www.rcsb.org/structure/9DFT).

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

*Describes the biological roles of ACAN (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:** p.Val705fs falls in the ks region. In Reactome, ACAN is annotated in disease pathway(s) including **Defective B4GALT1 causes B4GALT1-CDG (CDG-2d)**, **Defective CHST6 causes MCDC1**.

**Disease mechanism (Reactome):** ACAN loss or alteration is curated in [Defective B4GALT1 causes B4GALT1-CDG (CDG-2d)](https://reactome.org/content/detail/R-HSA-3656244), [Defective CHST6 causes MCDC1](https://reactome.org/content/detail/R-HSA-3656225), [Defective ST3GAL3 causes MCT12 and EIEE15](https://reactome.org/content/detail/R-HSA-3656243).

### Pathways affected {#pathways}

ACAN participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective B4GALT1 causes B4GALT1-CDG (CDG-2d)](https://reactome.org/content/detail/R-HSA-3656244) | curated |
| ⚕ [Defective CHST6 causes MCDC1](https://reactome.org/content/detail/R-HSA-3656225) | curated |
| ⚕ [Defective ST3GAL3 causes MCT12 and EIEE15](https://reactome.org/content/detail/R-HSA-3656243) | curated |
| [ECM proteoglycans](https://reactome.org/content/detail/R-HSA-3000178) | curated |
| [Keratan sulfate biosynthesis](https://reactome.org/content/detail/R-HSA-2022854) | curated |
| [Keratan sulfate degradation](https://reactome.org/content/detail/R-HSA-2022857) | curated |
| [Degradation of the extracellular matrix](https://reactome.org/content/detail/R-HSA-1474228) | electronic |

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-24.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| MVZ Medizinische Genetik Mainz | Pathogenic | criteria provided, single submitter | clinical testing | 2025-01-24 |

## Associated conditions {#conditions}

[short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans](https://sugi.bio/atlas/disease/short-stature-and-advanced-bone-age-with-or-without-early-onset-osteoarthritis-and-or-osteochondritis-dissecans/).

**Reported phenotype names (ClinVar):** Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans.

## Similar variants {#similar}

Related ACAN variant pages (same residue, condition, or type): [ACAN p.Gly366_Glu367insTer](/variant/acan-p-gly366-glu367inster), [ACAN p.Ala2277fs](/variant/acan-p-ala2277fs), [ACAN p.Arg668fs](/variant/acan-p-arg668fs), [ACAN p.Asp953fs](/variant/acan-p-asp953fs), [ACAN p.Gly554fs](/variant/acan-p-gly554fs), [ACAN p.Pro510_Glu511insAlaCysLeuArgThrGlyAlaValIleAlaSerPro](/variant/acan-p-pro510-glu511insalacysleuargthrglyalavalilealaserpro), [ACAN p.Val705Gly](/variant/acan-p-val705gly), [ACAN p.Val705=](/variant/acan-p-val705).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 3342274). 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.*