# NM_016356.5(DCDC2):c.12C>T (p.Ser4=)

https://sugi.bio/variant/dcdc2-p-ser4

## Summary

**DCDC2 p.Ser4= (c.12C>T)** is classified **Likely benign** in DCDC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-14). AlphaMissense: likely benign (0.1046); Very rare (popmax 0.00446%, eas); Associated with isolated neonatal sclerosing cholangitis.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00446%, eas)

## For patients & families {#patients}

This is a change in the DCDC2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, 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 |

**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.Ser4= |
| Coding change (HGVS c.) | c.12C>T |
| Variant type | single nucleotide variant |
| Location | chr6:24357739-24357739 (GRCh38) |
| ClinVar | [VCV3761554](https://www.ncbi.nlm.nih.gov/clinvar/variation/3761554/) |

**All HGVS expressions:** `NC_000006.11:g.24357967G>A`, `NC_000006.12:g.24357739G>A`, `NG_012829.2:g.30554C>T`, `NM_001195610.2:c.12C>T`, `NM_016356.5:c.12C>T`, `NR_174942.1:n.837G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1046)
- REVEL 0.036 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.237 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.067, GERP -0.077 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 12.99**. 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 looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.00446%** (eas) · FAF95 0.000739% · FAF99 0.000277% · 2/44,860 in the highest group · 8/1,459,970 alleles overall — very rare (popmax 0.00446%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00446% | 22,430 |
| European (non-Finnish) | 0.000509% | 196,560 |

*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.*

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-14.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-02-14 |

## 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, Sclerosing cholangitis, neonatal, Deafness, autosomal recessive 66.

### 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 3761554). 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.*