# NM_016356.5(DCDC2):c.454C>G (p.Pro152Ala)

https://sugi.bio/variant/dcdc2-p-pro152ala

## Summary

**DCDC2 p.Pro152Ala (c.454C>G)** is classified **Benign/Likely benign** in DCDC2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1332); Common (popmax 5.33%, sas) — too common for a highly-penetrant pathogenic allele; Associated with isolated neonatal sclerosing cholangitis.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs33914824 · 5 submitters · 2 linked conditions · AlphaMissense likely benign · common (popmax 5.33%, sas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the DCDC2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 5 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.Pro152Ala |
| Coding change (HGVS c.) | c.454C>G |
| MANE Select transcript | [NM_016356](https://www.ncbi.nlm.nih.gov/nuccore/NM_016356) |
| dbSNP | [rs33914824](https://www.ncbi.nlm.nih.gov/snp/rs33914824/) |
| Variant type | single nucleotide variant |
| Location | chr6:24301818-24301818 (GRCh38) |
| ClinVar | [VCV466326](https://www.ncbi.nlm.nih.gov/clinvar/variation/466326/) |

**All HGVS expressions:** `NC_000006.11:g.24302046G>C`, `NC_000006.12:g.24301818G>C`, `NG_012829.2:g.86475C>G`, `NM_001195610.2:c.454C>G`, `NM_016356.5:c.454C>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 5.33%, sas) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.1332)
- REVEL 0.441 (indeterminate)
- SaProt LLR -10.93 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate
- Conservation: phyloP 11.653, GERP 1.81, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.9**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. This allele is not in the release, so all four of its deltas are under 0.2. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, and here that is proven rather than inferred: a different substitution at this very position, G>A, IS in the release and scores Δ0.20 acceptor gain, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **5.33%** (sas) · FAF95 5.2% · FAF99 5.15% · 4,854/91,076 in the highest group · 63,178/1,614,066 alleles overall — common (popmax 5.33%, sas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 9.56% | 10 |
| Ashkenazi Jewish (not grpmax-eligible) | 5.8% | 17 |
| South Asian (grpmax) | 5.33% | 19 |
| Middle Eastern | 5.31% | 19 |
| Remaining individuals (not grpmax-eligible) | 4.27% | 23 |
| African / African-American | 4.13% | 24 |
| European (non-Finnish) | 3.98% | 25 |
| Admixed American | 2.8% | 36 |
| Finnish (not grpmax-eligible) | 1.7% | 59 |
| East Asian | 1.66% | 60 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **152** lies in a UniProt-annotated variant site (in); the doublecortin 2 domain.

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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (4 Benign, 1 Likely benign).

**Submission history:** 5 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2017-08-16 |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2019-02-26 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-05-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |

## 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, not specified, Sclerosing cholangitis, neonatal, Deafness, autosomal recessive 66, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related DCDC2 variant pages (same residue, condition, or type): [DCDC2 p.Pro152=](/variant/dcdc2-p-pro152), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 466326). 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.*