# NM_016356.5(DCDC2):c.1275G>T (p.Leu425=)

https://sugi.bio/variant/dcdc2-p-leu425

## Summary

**DCDC2 p.Leu425= (c.1275G>T)** is classified **Likely benign** in DCDC2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-10-24). Ultra-rare (popmax 0.015%, amr); Associated with isolated neonatal sclerosing cholangitis.

**At a glance:** Likely benign · review: Single submitter · rsID rs534996877 · 2 submitters · 2 linked conditions · ultra-rare (popmax 0.015%, amr)

## For patients & families {#patients}

This is a change in the DCDC2 gene that is classified as likely benign — not considered disease-causing, submitted by 2 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.Leu425= |
| Coding change (HGVS c.) | c.1275G>T |
| MANE Select transcript | [NM_016356](https://www.ncbi.nlm.nih.gov/nuccore/NM_016356) |
| dbSNP | [rs534996877](https://www.ncbi.nlm.nih.gov/snp/rs534996877/) |
| Variant type | single nucleotide variant |
| Location | chr6:24178381-24178381 (GRCh38) |
| ClinVar | [VCV2048632](https://www.ncbi.nlm.nih.gov/clinvar/variation/2048632/) |

**All HGVS expressions:** `NC_000006.11:g.24178609C>A`, `NC_000006.12:g.24178381C>A`, `NG_012829.2:g.209912G>T`, `NM_001195610.2:c.1275G>T`, `NM_016356.4:c.1275G>T`, `NM_016356.5:c.1275G>T`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -3.059, GERP -3.5 — fast-evolving / accelerated position
- CADD: **PHRED 0.166**. 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.*
- 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 **0.015%** (amr) · FAF95 0.00773% · FAF99 0.00578% · 9/60,024 in the highest group · 27/1,614,160 alleles overall — ultra-rare (popmax 0.015%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.015% | 6,669 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,508 |
| European (non-Finnish) | 0.00144% | 69,413 |

*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 **425** lies in a UniProt-annotated variant site (in nsc); the 'disordered' region.

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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-24.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2021–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-01-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-24 |

## 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, DCDC2-related disorder, DCDC2-related condition, Sclerosing cholangitis, neonatal, Deafness, autosomal recessive 66.

## 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 2048632). 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.*