# NM_005215.4(DCC):c.3944del (p.Pro1315fs)

https://sugi.bio/variant/dcc-p-pro1315fs

## Summary

**DCC p.Pro1315fs (c.3944del)** is classified **Pathogenic** in DCC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-25). Associated with gaze palsy, familial horizontal, with progressive scoliosis, 2.

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

## For patients & families {#patients}

This is a change in the DCC gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to gaze palsy, familial horizontal, with progressive scoliosis, 2.

*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 recessive |
| Age of onset (of this condition) | Adolescent, Childhood |
| Diagnostic panels | DCC is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Horizontal gaze palsy with progressive scoliosis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Scoliosis — Very frequent (99-80%)
- Kyphosis — Very frequent (99-80%)
- Horizontal supranuclear gaze palsy — Very frequent (99-80%)
- Microcephaly — Frequent (79-30%)
- Short neck — Frequent (79-30%)
- Strabismus — Frequent (79-30%)
- Visual impairment — Frequent (79-30%)
- Nystagmus — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016234/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DCC](https://sugi.bio/atlas/gene/DCC/) |
| Protein change (HGVS p.) | p.Pro1315fs |
| Coding change (HGVS c.) | c.3944del |
| MANE Select transcript | [NM_005215](https://www.ncbi.nlm.nih.gov/nuccore/NM_005215) |
| Variant type | Deletion |
| Location | chr18:53499339-53499339 (GRCh38) |
| ClinVar | [VCV4850760](https://www.ncbi.nlm.nih.gov/clinvar/variation/4850760/) |

**All HGVS expressions:** `LRG_1107:g.1164172del`, `LRG_1107t1:c.3944del`, `NC_000018.10:g.53499343del`, `NC_000018.9:g.51025713del`, `NG_013341.2:g.1164172del`, `NM_005215.4:c.3944del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 3.996, GERP 1.27, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.414, 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 27 of 29**, 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.

*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}

**DCC** population constraint: LOEUF 0.414, pLI 1, missense-Z 0.97556. *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):

- **mirror movements 1 and/or agenesis of the corpus callosum** — Definitive (AD)

## Protein context {#protein}

Residue **1315** lies in the 'disordered' region; a UniProt-annotated variant site (in mrmv1; likely pathogenic).

AlphaFold model confidence (whole protein): pLDDT 68.60, 26% of residues very-high.

**9 experimental structure(s)** (PDB): [2ED7](https://www.rcsb.org/structure/2ED7), [2ED8](https://www.rcsb.org/structure/2ED8), [2ED9](https://www.rcsb.org/structure/2ED9), [2EDB](https://www.rcsb.org/structure/2EDB), [2EDD](https://www.rcsb.org/structure/2EDD), [2EDE](https://www.rcsb.org/structure/2EDE).

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

*Describes the biological roles of DCC (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.*


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Caspase activation via Dependence Receptors in the absence of ligand](https://reactome.org/content/detail/R-HSA-418889) | curated |
| [DCC mediated attractive signaling](https://reactome.org/content/detail/R-HSA-418885) | electronic |
| [DSCAM interactions](https://reactome.org/content/detail/R-HSA-376172) | electronic |
| [Netrin mediated repulsion signals](https://reactome.org/content/detail/R-HSA-418886) | electronic |
| [Netrin-1 signaling](https://reactome.org/content/detail/R-HSA-373752) | electronic |
| [Regulation of commissural axon pathfinding by SLIT and ROBO](https://reactome.org/content/detail/R-HSA-428542) | electronic |
| [Role of second messengers in netrin-1 signaling](https://reactome.org/content/detail/R-HSA-418890) | electronic |

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-25.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Variantyx, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-25 |

## Associated conditions {#conditions}

[gaze palsy, familial horizontal, with progressive scoliosis, 2](https://sugi.bio/atlas/disease/gaze-palsy-familial-horizontal-with-progressive-scoliosis-2/).

**Reported phenotype names (ClinVar):** Gaze palsy, familial horizontal, with progressive scoliosis, 2, GAZE PALSY, FAMILIAL HORIZONTAL, WITH PROGRESSIVE SCOLIOSIS 2, WITH IMPAIRED INTELLECTUAL DEVELOPMENT, DEVELOPMENTAL SPLIT-BRAIN SYNDROME.

## Similar variants {#similar}

Related DCC variant pages (same residue, condition, or type): [DCC p.Val263fs](/variant/dcc-p-val263fs), [DCC p.Pro1315Ala](/variant/dcc-p-pro1315ala), [DCC c.31_91+7622del](/variant/dcc-c-31-91-plus-7622del), [DCC c.2053+13A>G](/variant/dcc-c-2053-plus-13a-g), [DCC c.2053+9T>C](/variant/dcc-c-2053-plus-9t-c), [DCC c.3130+10A>G](/variant/dcc-c-3130-plus-10a-g), [DCC c.91+7G>A](/variant/dcc-c-91-plus-7g-a), [DCC p.Arg201Gly](/variant/dcc-p-arg201gly).

### 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 4850760). 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.*