# NM_004385.5(VCAN):c.159A>G (p.Pro53=)

https://sugi.bio/variant/vcan-p-pro53

## Summary

**VCAN p.Pro53= (c.159A>G)** is classified **Likely benign** in VCAN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-05). Very rare (popmax 0.000424%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs1744932735 · 1 submitter · very rare (popmax 0.000424%, nfe)

## For patients & families {#patients}

This is a change in the VCAN gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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 | [VCAN](https://sugi.bio/atlas/gene/VCAN/) |
| Protein change (HGVS p.) | p.Pro53= |
| Coding change (HGVS c.) | c.159A>G |
| MANE Select transcript | [NM_004385](https://www.ncbi.nlm.nih.gov/nuccore/NM_004385) |
| dbSNP | [rs1744932735](https://www.ncbi.nlm.nih.gov/snp/rs1744932735/) |
| Variant type | single nucleotide variant |
| Location | chr5:83490186-83490186 (GRCh38) |
| ClinVar | [VCV1571098](https://www.ncbi.nlm.nih.gov/clinvar/variation/1571098/) |

**All HGVS expressions:** `NC_000005.10:g.83490186A>G`, `NC_000005.9:g.82786005A>G`, `NG_012682.1:g.23476A>G`, `NM_001126336.3:c.159A>G`, `NM_001164097.2:c.159A>G`, `NM_001164098.2:c.159A>G`, `NM_004385.5:c.159A>G`

## 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 0.639, GERP -1.25, phastCons 0.942 — weakly conserved position
- CADD: **PHRED 6.96**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>C, Δ0.33 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000424%** (nfe) · FAF95 0.000124% · FAF99 9e-05% · 5/1,180,030 in the highest group · 5/1,614,146 alleles overall — very rare (popmax 0.000424%, 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}

**VCAN** population constraint: LOEUF 0.223, pLI 1, missense-Z 2.6822; ClinGen dosage — haploinsufficiency 1/3, triplosensitivity -1/3. *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):

- **Wagner disease** — Definitive (AD)

## Protein context {#protein}

Residue **53** lies in the ig-like v-type domain.

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

*Describes the biological roles of VCAN (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:** VCAN's established molecular role includes protein tyrosine phosphatase activator activity. p.Pro53= falls in the ig-like v-type domain. In Reactome, VCAN is annotated in disease pathway(s) including **Defective B3GALT6 causes EDSP2 and SEMDJL1**, **Defective B3GAT3 causes JDSSDHD**.

**Disease mechanism (Reactome):** VCAN loss or alteration is curated in [Defective B3GALT6 causes EDSP2 and SEMDJL1](https://reactome.org/content/detail/R-HSA-4420332), [Defective B3GAT3 causes JDSSDHD](https://reactome.org/content/detail/R-HSA-3560801), [Defective B4GALT7 causes EDS, progeroid type](https://reactome.org/content/detail/R-HSA-3560783).

### Pathways affected {#pathways}

VCAN participates in **13 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective B3GALT6 causes EDSP2 and SEMDJL1](https://reactome.org/content/detail/R-HSA-4420332) | curated |
| ⚕ [Defective B3GAT3 causes JDSSDHD](https://reactome.org/content/detail/R-HSA-3560801) | curated |
| ⚕ [Defective B4GALT7 causes EDS, progeroid type](https://reactome.org/content/detail/R-HSA-3560783) | curated |
| ⚕ [Defective CHST14 causes EDS, musculocontractural type](https://reactome.org/content/detail/R-HSA-3595174) | curated |
| ⚕ [Defective CHST3 causes SEDCJD](https://reactome.org/content/detail/R-HSA-3595172) | curated |
| ⚕ [Defective CHSY1 causes TPBS](https://reactome.org/content/detail/R-HSA-3595177) | curated |
| [CS-GAG biosynthesis](https://reactome.org/content/detail/R-HSA-2022870) | curated |
| [CS/DS degradation](https://reactome.org/content/detail/R-HSA-2024101) | curated |
| [DS-GAG biosynthesis](https://reactome.org/content/detail/R-HSA-2022923) | curated |
| [ECM proteoglycans](https://reactome.org/content/detail/R-HSA-3000178) | curated |
| [Glycosaminoglycan-protein linkage region biosynthesis](https://reactome.org/content/detail/R-HSA-1971475) | curated |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protein tyrosine phosphatase activator activity.

**Biological process:** osteoblast differentiation, glial cell migration.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-05.

**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 | 2024-11-05 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related VCAN variant pages (same residue, condition, or type): [VCAN p.Pro53Ser](/variant/vcan-p-pro53ser), [VCAN c.4004-1G>A](/variant/vcan-c-4004-minus-1g-a), [VCAN c.4004-2A>C](/variant/vcan-c-4004-minus-2a-c), [VCAN c.4004-2A>G](/variant/vcan-c-4004-minus-2a-g), [VCAN c.4004-5T>C](/variant/vcan-c-4004-minus-5t-c), [VCAN c.9265+1G>C](/variant/vcan-c-9265-plus-1g-c), [VCAN c.9266-5G>A](/variant/vcan-c-9266-minus-5g-a), [VCAN c.9493+5G>A](/variant/vcan-c-9493-plus-5g-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 1571098). 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.*