# NM_005215.4(DCC):c.1784G>T (p.Ser595Ile)

https://sugi.bio/variant/dcc-p-ser595ile

## Summary

**DCC p.Ser595Ile (c.1784G>T)** is classified **Uncertain significance** in DCC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-15). AlphaMissense: likely benign (0.2846); Very rare (popmax 0.00331%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1427244860 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00331%, nfe)

## For patients & families {#patients}

This is a change in the DCC gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [DCC](https://sugi.bio/atlas/gene/DCC/) |
| Protein change (HGVS p.) | p.Ser595Ile |
| Coding change (HGVS c.) | c.1784G>T |
| MANE Select transcript | [NM_005215](https://www.ncbi.nlm.nih.gov/nuccore/NM_005215) |
| dbSNP | [rs1427244860](https://www.ncbi.nlm.nih.gov/snp/rs1427244860/) |
| Variant type | single nucleotide variant |
| Location | chr18:53207740-53207740 (GRCh38) |
| ClinVar | [VCV2483955](https://www.ncbi.nlm.nih.gov/clinvar/variation/2483955/) |

**All HGVS expressions:** `LRG_1107:g.872569G>T`, `LRG_1107t1:c.1784G>T`, `NC_000018.10:g.53207740G>T`, `NC_000018.9:g.50734110G>T`, `NG_013341.2:g.872569G>T`, `NM_005215.4:c.1784G>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.2846)
- REVEL 0.306 (indeterminate)
- SpliceAI predicts **acceptor gain** (Δ 0.27) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.35, GERP -4.48, phastCons 0.036 — weakly conserved position
- **SaProt:** withheld — SaProt scored this protein on a different isoform than AlphaMissense numbered the variant on, and the two diverge from residue 178, so a score under this position number would describe a different residue.
- CADD: **PHRED 19.41**. 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 0.98** across the covering region of the MANE Select transcript (52,340,788–53,530,591), spanning 1,189,803 bp. Chi-square p 0.4. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.27**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.27**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00331%** (nfe) · FAF95 0.00248% · FAF99 0.00217% · 39/1,178,940 in the highest group · 40/1,612,702 alleles overall — very rare (popmax 0.00331%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00331% | 30,229 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,438 |

*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 **595** lies in the fibronectin type-iii 2 domain; a UniProt-annotated variant site (in mrmv1; likely pathogenic); a β-strand.

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-02-15.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-02-15 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related DCC variant pages (same residue, condition, or type): [DCC p.Arg1021Ter](/variant/dcc-p-arg1021ter), [DCC p.Arg597Gln](/variant/dcc-p-arg597gln), [DCC p.Gly84Arg](/variant/dcc-p-gly84arg), [DCC p.Ile1080Val](/variant/dcc-p-ile1080val), [DCC p.Gln486Leu](/variant/dcc-p-gln486leu), [DCC p.Arg215Ter](/variant/dcc-p-arg215ter), [DCC c.3392+4G>A](/variant/dcc-c-3392-plus-4g-a), [DCC c.986-3C>T](/variant/dcc-c-986-minus-3c-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 2483955). 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.*