# NM_001195553.2(DCX):c.167G>C (p.Arg56Pro)

https://sugi.bio/variant/dcx-p-arg56pro

## Summary

**DCX p.Arg56Pro (c.167G>C)** is classified **Likely pathogenic** in DCX (ClinVar, Single submitter, 1 submitter; last evaluated 2014-04-02). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1; Associated with Ectopic tissue.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs587783525 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DCX gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Ectopic tissue.

*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 | [DCX](https://sugi.bio/atlas/gene/DCX/) |
| Protein change (HGVS p.) | p.Arg56Pro |
| Coding change (HGVS c.) | c.167G>C |
| MANE Select transcript | [NM_001195553](https://www.ncbi.nlm.nih.gov/nuccore/NM_001195553) |
| dbSNP | [rs587783525](https://www.ncbi.nlm.nih.gov/snp/rs587783525/) |
| Variant type | single nucleotide variant |
| Location | chrX:111410232-111410232 (GRCh38) |
| ClinVar | [VCV158431](https://www.ncbi.nlm.nih.gov/clinvar/variation/158431/) |

**All HGVS expressions:** `NC_000023.10:g.110653460C>G`, `NC_000023.11:g.111410232C>G`, `NG_011750.1:g.6947G>C`, `NM_000555.3:c.410G>C`, `NM_001195553.2:c.167G>C`, `NM_001369370.1:c.167G>C`, `NM_001369371.1:c.167G>C`, `NM_001369372.1:c.167G>C`, `NM_001369373.1:c.167G>C`, `NM_001369374.1:c.167G>C`, `NM_178151.3:c.167G>C`, `NM_178152.3:c.167G>C`, `NM_178153.3:c.167G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9998) — concordant with the pathogenic call
- REVEL 0.874 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.237 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **donor loss** (Δ 0.52) — consistent with the pathogenic call
- Conservation: phyloP 7.643, GERP 1.2, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 6%** most-pathogenic-predicted substitutions in DCX (of 2,158 modeled).
- CADD: **PHRED 29.3**. 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 0.31** across the covering region of the MANE Select transcript (111,333,066–111,410,398), spanning 77,332 bp — the region is depleted of missense variation. Chi-square p 4.4e-24. 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 **0.52**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.52**, acceptor gain **0.00**, donor gain **0.00**.
- 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}

**DCX** population constraint: ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **lissencephaly spectrum disorders** — Definitive (XL)

## Protein context {#protein}

Residue **56** lies in the doublecortin 1 domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 67.19, 10% of residues very-high.

**14 experimental structure(s)** (PDB): [1MJD](https://www.rcsb.org/structure/1MJD), [2BQQ](https://www.rcsb.org/structure/2BQQ), [2XRP](https://www.rcsb.org/structure/2XRP), [4ATU](https://www.rcsb.org/structure/4ATU), [5IKC](https://www.rcsb.org/structure/5IKC), [5IN7](https://www.rcsb.org/structure/5IN7).

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

*Describes the biological roles of DCX (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:** DCX's established molecular role includes microtubule binding. p.Arg56Pro falls in the doublecortin 1 domain.


### Pathways affected {#pathways}

DCX participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neurofascin interactions](https://reactome.org/content/detail/R-HSA-447043) | electronic |

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

**Molecular function:** microtubule binding, protein kinase binding.

**Biological process:** neuron migration.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2014-04-02.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely pathogenic | criteria provided, single submitter | clinical testing | 2014-04-02 |

## Associated conditions {#conditions}

[Ectopic tissue](https://sugi.bio/atlas/disease/ectopic-tissue/).

**Reported phenotype names (ClinVar):** Ectopic tissue, Heterotopia.

## Same-residue context {#hotspot}

Residue **56** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DCX p.Arg56Leu](/variant/dcx-p-arg56leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DCX variant pages (same residue, condition, or type): [DCX p.Arg56Leu](/variant/dcx-p-arg56leu), [DCX p.Ala204Asp](/variant/dcx-p-ala204asp), [DCX p.Ala251Ser](/variant/dcx-p-ala251ser), [DCX p.Arg186Cys](/variant/dcx-p-arg186cys), [DCX p.Arg192Trp](/variant/dcx-p-arg192trp), [DCX p.Arg196Cys](/variant/dcx-p-arg196cys), [DCX p.Arg59His](/variant/dcx-p-arg59his), [DCX p.Arg78Cys](/variant/dcx-p-arg78cys).

### 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 158431). 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.*