# NM_016356.5(DCDC2):c.463C>T (p.Arg155Cys)

https://sugi.bio/variant/dcdc2-p-arg155cys

## Summary

**DCDC2 p.Arg155Cys (c.463C>T)** is classified **Uncertain significance** in DCDC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-27). AlphaMissense: likely pathogenic (0.6949); Very rare (popmax 0.00878%, sas); Associated with isolated neonatal sclerosing cholangitis.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs368811969 · 3 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00878%, sas)

## For patients & families {#patients}

This is a change in the DCDC2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to isolated neonatal sclerosing cholangitis.

*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) | Neonatal |
| Diagnostic panels | DCDC2 is a diagnostic-grade gene on 3 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0021983/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DCDC2](https://sugi.bio/atlas/gene/DCDC2/) |
| Protein change (HGVS p.) | p.Arg155Cys |
| Coding change (HGVS c.) | c.463C>T |
| MANE Select transcript | [NM_016356](https://www.ncbi.nlm.nih.gov/nuccore/NM_016356) |
| dbSNP | [rs368811969](https://www.ncbi.nlm.nih.gov/snp/rs368811969/) |
| Variant type | single nucleotide variant |
| Location | chr6:24301809-24301809 (GRCh38) |
| ClinVar | [VCV2186477](https://www.ncbi.nlm.nih.gov/clinvar/variation/2186477/) |

**All HGVS expressions:** `NC_000006.11:g.24302037G>A`, `NC_000006.12:g.24301809G>A`, `NG_012829.2:g.86484C>T`, `NM_001195610.2:c.463C>T`, `NM_016356.4:c.463C>T`, `NM_016356.5:c.463C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.6949)
- REVEL 0.876 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.908 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 8.476, GERP 1.81, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. 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 (24,174,733–24,357,750), spanning 183,017 bp. Chi-square p 0.62. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.35 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Pangolin: Δ**0.23** (loss), gain 0.14 / loss 0.23. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00878%** (sas) · FAF95 0.00437% · FAF99 0.00312% · 8/91,086 in the highest group · 27/1,614,026 alleles overall — very rare (popmax 0.00878%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00878% | 11,386 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,244 |
| East Asian | 0.00223% | 44,886 |
| Admixed American | 0.00167% | 60,006 |
| European (non-Finnish) | 0.00127% | 78,669 |

*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}

**DCDC2** population constraint: LOEUF 1.062, pLI 1.1753e-09, missense-Z 0.58407. *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):

- **ciliopathy** — Definitive (AR)
- **nonsyndromic genetic hearing loss** — Limited (AR)

## Protein context {#protein}

Residue **155** lies in the doublecortin 2 domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 63.93, 17% of residues very-high.

**1 experimental structure(s)** (PDB): [2DNF](https://www.rcsb.org/structure/2DNF).

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-27.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2020–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-04-18 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-09-22 |

## Associated conditions {#conditions}

[isolated neonatal sclerosing cholangitis](https://sugi.bio/atlas/disease/isolated-neonatal-sclerosing-cholangitis/), [autosomal recessive nonsyndromic hearing loss 66](https://sugi.bio/atlas/disease/autosomal-recessive-nonsyndromic-hearing-loss-66/).

**Reported phenotype names (ClinVar):** Isolated neonatal sclerosing cholangitis, Autosomal recessive nonsyndromic hearing loss 66, not provided, Sclerosing cholangitis, neonatal, Deafness, autosomal recessive 66, none provided.

## Similar variants {#similar}

Related DCDC2 variant pages (same residue, condition, or type): [DCDC2 c.294-2A>G](/variant/dcdc2-c-294-minus-2a-g), [DCDC2 c.349-2A>G](/variant/dcdc2-c-349-minus-2a-g), [DCDC2 c.705-2A>G](/variant/dcdc2-c-705-minus-2a-g), [DCDC2 p.Leu297Ter](/variant/dcdc2-p-leu297ter), [DCDC2 p.Met1Arg](/variant/dcdc2-p-met1arg), [DCDC2 p.Ser128Ter](/variant/dcdc2-p-ser128ter), [DCDC2 p.Ala384Gly](/variant/dcdc2-p-ala384gly), [DCDC2 p.Ala93Asp](/variant/dcdc2-p-ala93asp).

### 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 2186477). 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.*