# NM_021044.4(DHH):c.30del (p.Cys11fs)

https://sugi.bio/variant/dhh-p-cys11fs

## Summary

**DHH p.Cys11fs (c.30del)** is classified **Likely pathogenic** in DHH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-20).

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter

## For patients & families {#patients}

This is a change in the DHH gene that is considered likely disease-causing, submitted by 1 submitter.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DHH](https://sugi.bio/atlas/gene/DHH/) |
| Protein change (HGVS p.) | p.Cys11fs |
| Coding change (HGVS c.) | c.30del |
| MANE Select transcript | [NM_021044](https://www.ncbi.nlm.nih.gov/nuccore/NM_021044) |
| Variant type | Deletion |
| Location | chr12:49094483-49094483 (GRCh38) |
| ClinVar | [VCV4081310](https://www.ncbi.nlm.nih.gov/clinvar/variation/4081310/) |

**All HGVS expressions:** `LRG_1273:g.5337del`, `LRG_1273t1:c.30del`, `NC_000012.11:g.49488266del`, `NC_000012.12:g.49094483del`, `NG_008973.2:g.5337del`, `NM_021044.4:c.30del`

## 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 11.15, GERP 2.21, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.999, pLI 0.0002665. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 3**, so the transcript is predicted to undergo NMD.
- 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.

*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}

**DHH** population constraint: LOEUF 0.999, pLI 0.0002665, missense-Z 1.425. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.87, 53% of residues very-high.

**5 experimental structure(s)** (PDB): [2WFQ](https://www.rcsb.org/structure/2WFQ), [2WFR](https://www.rcsb.org/structure/2WFR), [2WG3](https://www.rcsb.org/structure/2WG3), [3N1G](https://www.rcsb.org/structure/3N1G), [3N1Q](https://www.rcsb.org/structure/3N1Q).

## What this gene does {#gene-function}

*Describes the biological roles of DHH (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** DHH's established molecular role includes patched binding. In Reactome, DHH is annotated in disease pathway(s) including **HHAT G278V doesn't palmitoylate Hh-Np**.

**Disease mechanism (Reactome):** DHH loss or alteration is curated in [HHAT G278V doesn't palmitoylate Hh-Np](https://reactome.org/content/detail/R-HSA-5658034).

### Pathways affected {#pathways}

DHH participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [HHAT G278V doesn't palmitoylate Hh-Np](https://reactome.org/content/detail/R-HSA-5658034) | curated |
| [Activation of SMO](https://reactome.org/content/detail/R-HSA-5635838) | curated |
| [Hedgehog ligand biogenesis](https://reactome.org/content/detail/R-HSA-5358346) | curated |
| [Class B/2 (Secretin family receptors)](https://reactome.org/content/detail/R-HSA-373080) | electronic |
| [Hedgehog 'on' state](https://reactome.org/content/detail/R-HSA-5632684) | electronic |
| [Ligand-receptor interactions](https://reactome.org/content/detail/R-HSA-5632681) | electronic |
| [Release of Hh-Np from the secreting cell](https://reactome.org/content/detail/R-HSA-5362798) | electronic |
| [Transcriptional regulation of testis differentiation](https://reactome.org/content/detail/R-HSA-9690406) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** patched binding, calcium ion binding, zinc ion binding.

**Biological process:** positive regulation of smoothened signaling pathway.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-20.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-03-20 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related DHH variant pages (same residue, condition, or type): [DHH p.Asn337fs](/variant/dhh-p-asn337fs), [DHH c.303+133del](/variant/dhh-c-303-plus-133del), [DHH p.Leu363fs](/variant/dhh-p-leu363fs).

### 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 4081310). 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.*