# NM_001369268.1(ACAN):c.2789G>T (p.Ser930Ile)

https://sugi.bio/variant/acan-p-ser930ile

## Summary

**ACAN p.Ser930Ile (c.2789G>T)** is classified **Benign** in ACAN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-05-08). AlphaMissense: likely benign (0.1852); Common (popmax 64.6%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with osteochondritis dissecans.

**At a glance:** Benign · review: Multiple submitters · rsID rs938608 · 4 submitters · 4 linked conditions · AlphaMissense likely benign · common (popmax 64.6%, nfe) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the ACAN gene that is classified as benign — not considered disease-causing, submitted by 4 submitters, and is linked to 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) | Not applicable |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-5 / 10 000 (Europe) |
| Clinical trials | 23 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ACAN is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Osteochondritis dissecans** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Limitation of joint mobility — Very frequent (99-80%)
- Joint swelling — Very frequent (99-80%)
- Joint stiffness — Very frequent (99-80%)
- Abnormality of the knee — Very frequent (99-80%)
- Arthralgia — Very frequent (99-80%)
- Osteopenia — Frequent (79-30%)
- Abnormal joint morphology — Frequent (79-30%)
- Limited elbow extension — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012703/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.Ser930Ile |
| Coding change (HGVS c.) | c.2789G>T |
| MANE Select transcript | [NM_001369268](https://www.ncbi.nlm.nih.gov/nuccore/NM_001369268) |
| dbSNP | [rs938608](https://www.ncbi.nlm.nih.gov/snp/rs938608/) |
| Variant type | single nucleotide variant |
| Location | chr15:88855374-88855374 (GRCh38) |
| ClinVar | [VCV1188886](https://www.ncbi.nlm.nih.gov/clinvar/variation/1188886/) |

**All HGVS expressions:** `NC_000015.10:g.88855374G>T`, `NC_000015.9:g.89398605G>T`, `NG_012794.1:g.56932G>T`, `NM_001135.4:c.2789G>T`, `NM_001369268.1:c.2789G>T`, `NM_013227.4:c.2789G>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 64.6%, nfe) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.1852)
- REVEL 0.04 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.263 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.559, GERP -2.72 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.408**. 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.*
- Regional missense constraint: **o/e 1.00** across the covering region of the MANE Select transcript (88,836,207–88,855,487), spanning 19,280 bp. Chi-square p 0.97. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **64.6%** (nfe) · FAF95 64.5% · FAF99 64.4% · 761,811/1,179,086 in the highest group · 971,002/1,612,482 alleles overall — common (popmax 64.6%, nfe) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 65.7% | 2 |
| European (non-Finnish) (grpmax) | 64.6% | 2 |
| Ashkenazi Jewish (not grpmax-eligible) | 61.1% | 2 |
| Middle Eastern | 59.1% | 2 |
| Finnish (not grpmax-eligible) | 58.8% | 2 |
| Remaining individuals (not grpmax-eligible) | 58.3% | 2 |
| South Asian | 50.5% | 2 |
| African / African-American | 47.4% | 2 |
| Admixed American | 36.8% | 3 |
| East Asian | 21.2% | 5 |

Amish 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}

**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 **930** lies in a UniProt-annotated variant site (in); the 'disordered' region; the 'cs-1' 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.Ser930Ile falls in the disordered 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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-05-08.

**Submitter consensus:** unanimous (7/7 Benign).

**Submission history:** 7 submissions (2021–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-12-05 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-07-14 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2026-05-08 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-27 |

## Associated conditions {#conditions}

[osteochondritis dissecans](https://sugi.bio/atlas/disease/osteochondritis-dissecans/), [spondyloepiphyseal dysplasia, Kimberley type](https://sugi.bio/atlas/disease/spondyloepiphyseal-dysplasia-kimberley-type/), [spondyloepimetaphyseal dysplasia, aggrecan type](https://sugi.bio/atlas/disease/spondyloepimetaphyseal-dysplasia-aggrecan-type/), [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):** Osteochondritis dissecans, Spondyloepiphyseal dysplasia, Kimberley type, Spondyloepimetaphyseal dysplasia, aggrecan type, Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans, not provided, not specified, none provided, AllHighlyPenetrant, SEMD, AGGRECAN TYPE.

## Similar variants {#similar}

Related ACAN variant pages (same residue, condition, or type): [ACAN c.1733-2A>G](/variant/acan-c-1733-minus-2a-g), [ACAN c.7302+1G>A](/variant/acan-c-7302-plus-1g-a), [ACAN p.Arg236Ter](/variant/acan-p-arg236ter), [ACAN p.Arg675Ter](/variant/acan-p-arg675ter), [ACAN p.Asp2419Asn](/variant/acan-p-asp2419asn), [ACAN p.Glu254Ter](/variant/acan-p-glu254ter), [ACAN p.Lys74Ter](/variant/acan-p-lys74ter), [ACAN p.Trp377Ter](/variant/acan-p-trp377ter).

### 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 1188886). 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.*