# NM_198968.4(DZIP1):c.1844A>T (p.Asp615Val)

https://sugi.bio/variant/dzip1-p-asp615val

## Summary

**DZIP1 p.Asp615Val (c.1844A>T)** is classified **Uncertain significance** in DZIP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-03). AlphaMissense: likely benign (0.1136); Very rare (popmax 0.0011%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.0011%, nfe)

## For patients & families {#patients}

This is a change in the DZIP1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [DZIP1](https://sugi.bio/atlas/gene/DZIP1/) |
| Protein change (HGVS p.) | p.Asp615Val |
| Coding change (HGVS c.) | c.1844A>T |
| MANE Select transcript | [NM_198968](https://www.ncbi.nlm.nih.gov/nuccore/NM_198968) |
| Variant type | single nucleotide variant |
| Location | chr13:95589932-95589932 (GRCh38) |
| ClinVar | [VCV4246033](https://www.ncbi.nlm.nih.gov/clinvar/variation/4246033/) |

**All HGVS expressions:** `NC_000013.10:g.96242186T>A`, `NC_000013.11:g.95589932T>A`, `NM_014934.5:c.1787A>T`, `NM_198968.4:c.1844A>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1136)
- REVEL 0.189 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.968 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.36) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.851, GERP 2.5, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.8**. 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 0.97** across the covering region of the MANE Select transcript (95,582,237–95,642,029), spanning 59,792 bp. Chi-square p 0.38. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.36**, donor loss **0.00**, acceptor gain **0.13**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.36**, donor loss **0.00**, acceptor gain **0.13**, donor gain **0.00**.
- Pangolin: Δ**0.44** (loss), gain 0.16 / loss 0.44. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (nfe) · FAF95 0.000615% · FAF99 0.000474% · 13/1,179,748 in the highest group · 16/1,613,184 alleles overall — very rare (popmax 0.0011%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,815 |
| European (non-Finnish) (grpmax) | 0.0011% | 90,750 |

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}

**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 **615** lies in a UniProt-annotated variant site (in spgf47; decreased protein abundance; changed ciliary basal body organization; loss of sperm flagellum assembly); the 'mediates interaction with gdi2 and rab8a' 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.Asp615Val falls in the mediates interaction with gdi2 and rab8a 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-03.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-03 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related DZIP1 variant pages (same residue, condition, or type): [DZIP1 p.His262Arg](/variant/dzip1-p-his262arg), [DZIP1 p.Met664Leu](/variant/dzip1-p-met664leu), [DZIP1 p.Thr222=](/variant/dzip1-p-thr222), [DZIP1 p.Ala124Val](/variant/dzip1-p-ala124val), [DZIP1 p.Ala211Ser](/variant/dzip1-p-ala211ser), [DZIP1 p.Ala265Gly](/variant/dzip1-p-ala265gly), [DZIP1 p.Ala32Val](/variant/dzip1-p-ala32val), [DZIP1 p.Ala380Gly](/variant/dzip1-p-ala380gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 4246033). 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.*