# NM_005215.4(DCC):c.67T>C (p.Phe23Leu)

https://sugi.bio/variant/dcc-p-phe23leu

## Summary

**DCC p.Phe23Leu (c.67T>C)** is classified **Benign** in DCC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-28). AlphaMissense: likely pathogenic (0.5796); Common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele; Associated with gaze palsy, familial horizontal, with progressive scoliosis, 2.

**At a glance:** Benign · review: Multiple submitters · rsID rs9951523 · 3 submitters · 2 linked conditions · AlphaMissense likely pathogenic · common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the DCC gene that is classified as benign — not considered disease-causing, submitted by 3 submitters, 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.Phe23Leu |
| Coding change (HGVS c.) | c.67T>C |
| MANE Select transcript | [NM_005215](https://www.ncbi.nlm.nih.gov/nuccore/NM_005215) |
| dbSNP | [rs9951523](https://www.ncbi.nlm.nih.gov/snp/rs9951523/) |
| Variant type | single nucleotide variant |
| Location | chr18:52340854-52340854 (GRCh38) |
| ClinVar | [VCV1255454](https://www.ncbi.nlm.nih.gov/clinvar/variation/1255454/) |

**All HGVS expressions:** `LRG_1107:g.5683T>C`, `LRG_1107t1:c.67T>C`, `NC_000018.10:g.52340854T>C`, `NC_000018.9:g.49867224T>C`, `NG_013341.2:g.5683T>C`, `NM_005215.4:c.67T>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely pathogenic** (0.5796)
- REVEL 0.099 (moderately benign-leaning) — differs from AlphaMissense
- SaProt LLR -4.434 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- Conservation: phyloP 2.669, GERP -0.729, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 18.55**. 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 (gnomAD v4.1): grpmax **100%** (eas) · FAF95 99.3% · FAF99 99.1% · 44,833/44,838 in the highest group · 1,591,522/1,613,996 alleles overall — common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 100% | 1 |
| South Asian | 99.9% | 1 |
| African / African-American | 99.8% | 1 |
| Admixed American | 99.3% | 1 |
| Middle Eastern | 98.9% | 1 |
| Remaining individuals (not grpmax-eligible) | 98.7% | 1 |
| European (non-Finnish) | 98.6% | 1 |
| Amish (not grpmax-eligible) | 97.9% | 1 |
| Ashkenazi Jewish (not grpmax-eligible) | 97.4% | 1 |
| Finnish (not grpmax-eligible) | 95.1% | 1 |

*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 **23** lies in a UniProt-annotated variant site (in).

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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-11-28.

**Submitter consensus:** unanimous (4/4 Benign).

**Submission history:** 4 submissions (2021–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-07-30 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-28 |

## Associated conditions {#conditions}

[gaze palsy, familial horizontal, with progressive scoliosis, 2](https://sugi.bio/atlas/disease/gaze-palsy-familial-horizontal-with-progressive-scoliosis-2/), MONDO:0008002.

**Reported phenotype names (ClinVar):** Gaze palsy, familial horizontal, with progressive scoliosis, 2, Mirror movements 1, not provided, not specified, AllHighlyPenetrant, DEVELOPMENTAL SPLIT-BRAIN SYNDROME, GAZE PALSY, FAMILIAL HORIZONTAL, WITH PROGRESSIVE SCOLIOSIS 2, WITH IMPAIRED INTELLECTUAL DEVELOPMENT, none provided.

## Similar variants {#similar}

Related DCC variant pages (same residue, condition, or type): [DCC p.Arg1025Ter](/variant/dcc-p-arg1025ter), [DCC p.Arg275Ter](/variant/dcc-p-arg275ter), [DCC p.Arg879Ter](/variant/dcc-p-arg879ter), [DCC p.Gly803Arg](/variant/dcc-p-gly803arg), [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).

### 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 1255454). 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.*