# NM_198968.4(DZIP1):c.2248dup (p.Val750fs)

https://sugi.bio/variant/dzip1-p-val750fs

## Summary

**DZIP1 p.Val750fs (c.2248dup)** is classified **Likely pathogenic** in DZIP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-08). Associated with spermatogenic failure 47.

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

## For patients & families {#patients}

This is a change in the DZIP1 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to spermatogenic failure 47.

*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 | [DZIP1](https://sugi.bio/atlas/gene/DZIP1/) |
| Protein change (HGVS p.) | p.Val750fs |
| Coding change (HGVS c.) | c.2248dup |
| MANE Select transcript | [NM_198968](https://www.ncbi.nlm.nih.gov/nuccore/NM_198968) |
| Variant type | Duplication |
| Location | chr13:95586106-95586107 (GRCh38) |
| ClinVar | [VCV4845739](https://www.ncbi.nlm.nih.gov/clinvar/variation/4845739/) |

**All HGVS expressions:** `NC_000013.10:g.96238361dup`, `NC_000013.11:g.95586107dup`, `NM_014934.5:c.2191dup`, `NM_198968.4:c.2248dup`, `NM_198968.4:c.2248dupG`

## 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 5.336, GERP -0.063, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.01, pLI 1.1751e-23. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 21 of 23**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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}

**DZIP1** population constraint: LOEUF 1.01, pLI 1.1751e-23, missense-Z 0.53707. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **750** lies in a UniProt-annotated variant site (in spgf47; decreased protein abundance; changed ciliary basal body organization; loss of sperm flagellum assembly); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 65.55, 27% of residues very-high.

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

*Describes the biological roles of DZIP1 (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:** DZIP1's established molecular role includes molecular adaptor activity. p.Val750fs falls in the disordered region.


### Pathways affected {#pathways}

DZIP1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Hedgehog 'on' state](https://reactome.org/content/detail/R-HSA-5632684) | other |

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

**Molecular function:** molecular adaptor activity, BBSome binding.

**Biological process:** germ cell development, spermatogenesis, heart development, ciliary basal body organization, cilium assembly, sperm flagellum assembly.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-08.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| First Genomix Gene Laboratory, Genetic Diagnostics Department | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-01-08 |

## Associated conditions {#conditions}

[spermatogenic failure 47](https://sugi.bio/atlas/disease/spermatogenic-failure-47/).

**Reported phenotype names (ClinVar):** Spermatogenic failure 47.

## Similar variants {#similar}

Related DZIP1 variant pages (same residue, condition, or type): [DZIP1 p.His262Arg](/variant/dzip1-p-his262arg), [DZIP1 p.Ser369fs](/variant/dzip1-p-ser369fs), [DZIP1 p.Ser24Arg](/variant/dzip1-p-ser24arg), [DZIP1 p.Arg63Gln](/variant/dzip1-p-arg63gln), [DZIP1 p.Tyr230Ter](/variant/dzip1-p-tyr230ter), [DZIP1 c.37-5dup](/variant/dzip1-c-37-minus-5dup).

### 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 4845739). 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.*