# NM_005215.4(DCC):c.4124C>A (p.Pro1375His)

https://sugi.bio/variant/dcc-p-pro1375his

## Summary

**DCC p.Pro1375His (c.4124C>A)** is classified **Pathogenic** in DCC (ClinVar, No assertion criteria, 1 submitter; last evaluated 1994-02-01). AlphaMissense: likely benign (0.2512); Absent from gnomAD v4.1; Associated with colon carcinoma.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs387906555 · 1 submitter · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DCC gene that is reported as disease-causing, though the computational evidence is not fully concordant, submitted by 1 submitter, and is linked to colon carcinoma.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 1091 registered for this condition — see ClinicalTrials.gov |

**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.Pro1375His |
| Coding change (HGVS c.) | c.4124C>A |
| MANE Select transcript | [NM_005215](https://www.ncbi.nlm.nih.gov/nuccore/NM_005215) |
| dbSNP | [rs387906555](https://www.ncbi.nlm.nih.gov/snp/rs387906555/) |
| Variant type | single nucleotide variant |
| Location | chr18:53526629-53526629 (GRCh38) |
| ClinVar | [VCV17074](https://www.ncbi.nlm.nih.gov/clinvar/variation/17074/) |

**All HGVS expressions:** `LRG_1107:g.1191458C>A`, `LRG_1107t1:c.4124C>A`, `NC_000018.10:g.53526629C>A`, `NC_000018.9:g.51052999C>A`, `NG_013341.2:g.1191458C>A`, `NM_005215.4:c.4124C>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.2512) — ⚠ discordant with the pathogenic call
- REVEL 0.093 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.647 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 7.611, GERP 1.8, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.3**. 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: **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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **1375** lies in a UniProt-annotated variant site (in mrmv1; likely pathogenic); a UniProt-annotated variant site (in a colorectal carcinoma).

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 No assertion criteria *(no assertion criteria provided)*, last evaluated 1994-02-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1994-02-01 |

## Associated conditions {#conditions}

[colon carcinoma](https://sugi.bio/atlas/disease/colon-carcinoma/).

**Reported phenotype names (ClinVar):** Carcinoma of colon, Colon carcinoma, Colonic carcinoma.

## Similar variants {#similar}

Related DCC variant pages (same residue, condition, or type): [DCC p.Arg1021Ter](/variant/dcc-p-arg1021ter), [DCC p.Arg1025Ter](/variant/dcc-p-arg1025ter), [DCC p.Arg275Ter](/variant/dcc-p-arg275ter), [DCC p.Arg879Ter](/variant/dcc-p-arg879ter), [DCC c.3620-2A>G](/variant/dcc-c-3620-minus-2a-g), [DCC p.Arg597Gln](/variant/dcc-p-arg597gln), [DCC p.Gly1294Arg](/variant/dcc-p-gly1294arg), [DCC p.Gly55Arg](/variant/dcc-p-gly55arg).

### 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 17074). 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.*