# NM_001369268.1(ACAN):c.2326del (p.Ser776fs)

https://sugi.bio/variant/acan-p-ser776fs

## Summary

**ACAN p.Ser776fs (c.2326del)** is classified **Likely pathogenic** in ACAN (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-27). Very rare (popmax 8.58e-05%, nfe); Associated with ACAN-related disorder.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2141602054 · 1 submitter · 1 linked condition · very rare (popmax 8.58e-05%, nfe)

## For patients & families {#patients}

This is a change in the ACAN gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to ACAN-related disorder.

*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 | [ACAN](https://sugi.bio/atlas/gene/ACAN/) |
| Protein change (HGVS p.) | p.Ser776fs |
| Coding change (HGVS c.) | c.2326del |
| MANE Select transcript | [NM_001369268](https://www.ncbi.nlm.nih.gov/nuccore/NM_001369268) |
| dbSNP | [rs2141602054](https://www.ncbi.nlm.nih.gov/snp/rs2141602054/) |
| Variant type | Deletion |
| Location | chr15:88854910-88854910 (GRCh38) |
| ClinVar | [VCV1224465](https://www.ncbi.nlm.nih.gov/clinvar/variation/1224465/) |

**All HGVS expressions:** `NC_000015.10:g.88854911del`, `NC_000015.9:g.89398142del`, `NG_012794.1:g.56469del`, `NM_001135.4:c.2326del`, `NM_001369268.1:c.2326del`, `NM_013227.4:c.2326del`

## 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 1.081, GERP -3.18, phastCons 0.009 — 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 12 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 deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.58e-05%** (nfe) · 1/1,165,942 in the highest group · 1/1,427,292 alleles overall — very rare (popmax 8.58e-05%, nfe).

*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 **776** lies in the 'ks' region; the 'disordered' region; the '12 x 6 aa approximate tandem repeats of e-[gve]-p-[sfy]-[apt]-[tsp]' 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.Ser776fs 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-05-27.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-05-27 |

## Associated conditions {#conditions}

[ACAN-related disorder](https://sugi.bio/atlas/disease/acan-related-disorder/).

**Reported phenotype names (ClinVar):** ACAN-related disorder, ACAN-related condition, ACAN-related disorders.

## Similar variants {#similar}

Related ACAN variant pages (same residue, condition, or type): [ACAN p.Asn108fs](/variant/acan-p-asn108fs), [ACAN p.Ala2139fs](/variant/acan-p-ala2139fs), [ACAN p.Arg173fs](/variant/acan-p-arg173fs), [ACAN p.Asp865fs](/variant/acan-p-asp865fs), [ACAN p.Gln1618fs](/variant/acan-p-gln1618fs), [ACAN p.Gly998fs](/variant/acan-p-gly998fs), [ACAN p.Ile424fs](/variant/acan-p-ile424fs), [ACAN p.Pro2059fs](/variant/acan-p-pro2059fs).

### 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 1224465). 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.*