# NM_001369268.1(ACAN):c.1530G>A (p.Pro510=)

https://sugi.bio/variant/acan-p-pro510

## Summary

**ACAN p.Pro510= (c.1530G>A)** is classified **Benign** in ACAN (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-05-09). Common (popmax 9.96%, afr) — too common for a highly-penetrant pathogenic allele; Associated with short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans.

**At a glance:** Benign · review: Multiple submitters · rsID rs34637731 · 6 submitters · 3 linked conditions · common (popmax 9.96%, afr) — 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 6 submitters, 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.Pro510= |
| Coding change (HGVS c.) | c.1530G>A |
| MANE Select transcript | [NM_001369268](https://www.ncbi.nlm.nih.gov/nuccore/NM_001369268) |
| dbSNP | [rs34637731](https://www.ncbi.nlm.nih.gov/snp/rs34637731/) |
| Variant type | single nucleotide variant |
| Location | chr15:88847343-88847343 (GRCh38) |
| ClinVar | [VCV284338](https://www.ncbi.nlm.nih.gov/clinvar/variation/284338/) |

**All HGVS expressions:** `NC_000015.10:g.88847343G>A`, `NC_000015.9:g.89390574G>A`, `NG_012794.1:g.48901G>A`, `NM_001135.4:c.1530G>A`, `NM_001369268.1:c.1530G>A`, `NM_013227.4:c.1530G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 9.96%, afr) — too common for a highly-penetrant pathogenic allele.

- **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 -20, GERP -3.74 — fast-evolving / accelerated position
- CADD: **PHRED 0.026**. 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: **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 **9.96%** (afr) · FAF95 9.78% · FAF99 9.7% · 7,415/74,412 in the highest group · 8,492/1,585,858 alleles overall — common (popmax 9.96%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 9.96% | 10 |
| Remaining individuals (not grpmax-eligible) | 0.696% | 144 |
| Admixed American | 0.611% | 164 |
| Middle Eastern | 0.475% | 211 |
| South Asian | 0.0301% | 3,326 |
| European (non-Finnish) | 0.0213% | 4,687 |
| East Asian | 0.00921% | 10,862 |

*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 **510** lies in a disulfide bond; the link 3 domain; the 'g2-b' 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.Pro510= falls in the link 3 domain. 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 2026-05-09.

**Submitter consensus:** unanimous (8/8 Benign).

**Submission history:** 8 submissions (2015–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2015-11-18 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-07-14 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-12-05 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2026-05-09 |

## 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/), [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/).

**Reported phenotype names (ClinVar):** Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans, not specified, not provided, Spondyloepiphyseal dysplasia, Kimberley type, Spondyloepimetaphyseal dysplasia, aggrecan type, none provided, SEMD, AGGRECAN TYPE, AllHighlyPenetrant.

## Similar variants {#similar}

Related ACAN variant pages (same residue, condition, or type): [ACAN p.Pro510_Glu511insAlaCysLeuArgThrGlyAlaValIleAlaSerPro](/variant/acan-p-pro510-glu511insalacysleuargthrglyalavalilealaserpro), [ACAN p.Pro510Leu](/variant/acan-p-pro510leu), [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).

### 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 284338). 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.*