# NM_016356.5(DCDC2):c.289_292del (p.Leu97fs)

https://sugi.bio/variant/dcdc2-p-leu97fs

## Summary

**DCDC2 p.Leu97fs (c.289_292del)** is classified **Likely pathogenic** in DCDC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-05). Very rare (popmax 0.00307%, nfe); Associated with nephronophthisis 19.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 3 linked conditions · very rare (popmax 0.00307%, nfe)

## For patients & families {#patients}

This is a change in the DCDC2 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to nephronophthisis 19.

*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) | Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Finland) |
| Diagnostic panels | DCDC2 is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Nephronophthisis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Renal insufficiency — Frequent (79-30%)
- Anemia — Frequent (79-30%)
- Abnormality of retinal pigmentation — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018081/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.Leu97fs |
| Coding change (HGVS c.) | c.289_292del |
| MANE Select transcript | [NM_016356](https://www.ncbi.nlm.nih.gov/nuccore/NM_016356) |
| Variant type | Deletion |
| Location | chr6:24357459-24357462 (GRCh38) |
| ClinVar | [VCV3593429](https://www.ncbi.nlm.nih.gov/clinvar/variation/3593429/) |

**All HGVS expressions:** `NC_000006.11:g.24357688_24357691del`, `NC_000006.12:g.24357460_24357463del`, `NG_012829.2:g.30831_30834del`, `NM_001195610.2:c.289_292del`, `NM_016356.5:c.289_292del`, `NR_174942.1:n.558_561del`

## Computational & population evidence {#evidence}

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

- **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 6.1, GERP 2.03, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.062, pLI 1.1753e-09. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 10**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 34.0**. 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.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00307%** (nfe) · FAF95 0.00225% · FAF99 0.002% · 36/1,171,476 in the highest group · 39/1,599,124 alleles overall — very rare (popmax 0.00307%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00486% | 20,575 |
| European (non-Finnish) (grpmax) | 0.00307% | 32,541 |

Remaining individuals 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 **97** lies in the doublecortin 1 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-05.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-02-05 |

## Associated conditions {#conditions}

[nephronophthisis 19](https://sugi.bio/atlas/disease/nephronophthisis-19/), [autosomal recessive nonsyndromic hearing loss 66](https://sugi.bio/atlas/disease/autosomal-recessive-nonsyndromic-hearing-loss-66/), [isolated neonatal sclerosing cholangitis](https://sugi.bio/atlas/disease/isolated-neonatal-sclerosing-cholangitis/).

**Reported phenotype names (ClinVar):** Nephronophthisis 19, Autosomal recessive nonsyndromic hearing loss 66, Isolated neonatal sclerosing cholangitis, Deafness, autosomal recessive 66, Sclerosing cholangitis, neonatal.

## Similar variants {#similar}

Related DCDC2 variant pages (same residue, condition, or type): [DCDC2 p.Gly315fs](/variant/dcdc2-p-gly315fs), [DCDC2 c.923-283_1023+141del](/variant/dcdc2-c-923-minus-283-1023-plus-141del), [DCDC2 p.Glu222fs](/variant/dcdc2-p-glu222fs), [DCDC2 p.Leu179fs](/variant/dcdc2-p-leu179fs), [DCDC2 p.Lys298fs](/variant/dcdc2-p-lys298fs), [DCDC2 c.705-11del](/variant/dcdc2-c-705-minus-11del), [DCDC2 c.923-12_923-9del](/variant/dcdc2-c-923-minus-12-923-minus-9del), [DCDC2 c.426_557del](/variant/dcdc2-c-426-557del).

### 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 3593429). 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.*