# NM_016356.5(DCDC2):c.543C>T (p.Ser181=)

https://sugi.bio/variant/dcdc2-p-ser181

## Summary

**DCDC2 p.Ser181= (c.543C>T)** is classified **Conflicting classifications of pathogenicity** in DCDC2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-29). Ultra-rare (popmax 0.04%, amr); Associated with autosomal recessive nonsyndromic hearing loss 66.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs141060456 · 4 submitters · 2 linked conditions · ultra-rare (popmax 0.04%, amr)

## For patients & families {#patients}

This is a change in the DCDC2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to autosomal recessive nonsyndromic hearing loss 66.

*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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022621/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.Ser181= |
| Coding change (HGVS c.) | c.543C>T |
| MANE Select transcript | [NM_016356](https://www.ncbi.nlm.nih.gov/nuccore/NM_016356) |
| dbSNP | [rs141060456](https://www.ncbi.nlm.nih.gov/snp/rs141060456/) |
| Variant type | single nucleotide variant |
| Location | chr6:24301729-24301729 (GRCh38) |
| ClinVar | [VCV595441](https://www.ncbi.nlm.nih.gov/clinvar/variation/595441/) |

**All HGVS expressions:** `NC_000006.11:g.24301957G>A`, `NC_000006.12:g.24301729G>A`, `NG_012829.2:g.86564C>T`, `NM_001195610.2:c.543C>T`, `NM_016356.5:c.543C>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 -0.993, GERP -3.61 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.382**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.20 donor 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.*
- Population frequency (gnomAD v4.1): grpmax **0.04%** (amr) · FAF95 0.0276% · FAF99 0.0234% · 24/59,978 in the highest group · 125/1,613,920 alleles overall — ultra-rare (popmax 0.04%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.04% | 2,499 |
| Middle Eastern | 0.0329% | 3,042 |
| Remaining individuals (not grpmax-eligible) | 0.016% | 6,248 |
| South Asian | 0.011% | 9,107 |
| European (non-Finnish) | 0.00619% | 16,164 |
| African / African-American | 0.00401% | 24,963 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,608 |
| East Asian | 0.00223% | 44,888 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,010 |

*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 **181** lies 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-09-29.

**Submitter consensus:** conflicting (3 Likely benign, 1 Uncertain significance).

**Submission history:** 4 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-12-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-29 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2023-07-20 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-05-23 |

## Associated conditions {#conditions}

[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):** Autosomal recessive nonsyndromic hearing loss 66, not provided, Isolated neonatal sclerosing cholangitis, DCDC2-related disorder, not specified, Deafness, autosomal recessive 66, Sclerosing cholangitis, neonatal, AllHighlyPenetrant, none provided, DCDC2-related condition.

## Similar variants {#similar}

Related DCDC2 variant pages (same residue, condition, or type): [DCDC2 p.Ser181Arg](/variant/dcdc2-p-ser181arg), [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 2026-10-11); 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 595441). 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.*