# NM_001321209.2(DPY30):c.53A>C (p.His18Pro)

https://sugi.bio/variant/dpy30-p-his18pro

## Summary

**DPY30 p.His18Pro (c.53A>C)** is classified **Uncertain significance** in DPY30 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: ambiguous (0.3871); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DPY30 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 | [DPY30](https://sugi.bio/atlas/gene/DPY30/) |
| Protein change (HGVS p.) | p.His18Pro |
| Coding change (HGVS c.) | c.53A>C |
| MANE Select transcript | [NM_001321209](https://www.ncbi.nlm.nih.gov/nuccore/NM_001321209) |
| Variant type | single nucleotide variant |
| Location | chr2:32039310-32039310 (GRCh38) |
| ClinVar | [VCV4662050](https://www.ncbi.nlm.nih.gov/clinvar/variation/4662050/) |

**All HGVS expressions:** `NC_000002.11:g.32264379T>G`, `NC_000002.12:g.32039310T>G`, `NM_001321209.2:c.53A>C`, `NM_001321210.2:c.53A>C`, `NM_032574.4:c.53A>C`, `NR_135585.2:n.162A>C`, `NR_135587.1:n.192A>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.3871) — no call either way
- REVEL 0.217 (benign-leaning)
- SaProt LLR -4.793 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense makes no call
- Conservation: phyloP 7.592, GERP 1.62, phastCons 1 — highly conserved
- CADD: **PHRED 24.9**. 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 0.73** across the covering region of the MANE Select transcript (32,029,637–32,039,456), spanning 9,819 bp. Chi-square p 0.021. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**DPY30** population constraint: LOEUF 0.747, pLI 0.46037, missense-Z 1.4465. *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 **18** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 75.98, 48% of residues very-high.

**12 experimental structure(s)** (PDB): [3G36](https://www.rcsb.org/structure/3G36), [4RIQ](https://www.rcsb.org/structure/4RIQ), [4RT4](https://www.rcsb.org/structure/4RT4), [4RTA](https://www.rcsb.org/structure/4RTA), [6E2H](https://www.rcsb.org/structure/6E2H), [6PWV](https://www.rcsb.org/structure/6PWV).

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

*Describes the biological roles of DPY30 (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:** DPY30's established molecular role includes identical protein binding. p.His18Pro falls in the disordered region. In Reactome, DPY30 is annotated in disease pathway(s) including **Loss of Function of KMT2D in MLL4 Complex Formation in Kabuki Syndrome**.

**Disease mechanism (Reactome):** DPY30 loss or alteration is curated in [Loss of Function of KMT2D in MLL4 Complex Formation in Kabuki Syndrome](https://reactome.org/content/detail/R-HSA-9944997).

### Pathways affected {#pathways}

DPY30 participates in **12 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Loss of Function of KMT2D in MLL4 Complex Formation in Kabuki Syndrome](https://reactome.org/content/detail/R-HSA-9944997) | curated |
| [Deactivation of the beta-catenin transactivating complex](https://reactome.org/content/detail/R-HSA-3769402) | curated |
| [Epigenetic regulation of gene expression by MLL3 and MLL4 complexes](https://reactome.org/content/detail/R-HSA-9818564) | curated |
| [Formation of WDR5-containing histone-modifying complexes](https://reactome.org/content/detail/R-HSA-9772755) | curated |
| [Formation of the beta-catenin:TCF transactivating complex](https://reactome.org/content/detail/R-HSA-201722) | curated |
| [PKMTs methylate histone lysines](https://reactome.org/content/detail/R-HSA-3214841) | curated |
| [RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function](https://reactome.org/content/detail/R-HSA-8936459) | curated |
| [Regulation of PD-L1(CD274) transcription](https://reactome.org/content/detail/R-HSA-9909649) | curated |
| [Activation of anterior HOX genes in hindbrain development during early embryogenesis](https://reactome.org/content/detail/R-HSA-5617472) | electronic |
| [Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)](https://reactome.org/content/detail/R-HSA-9976102) | electronic |
| [MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis](https://reactome.org/content/detail/R-HSA-9841922) | electronic |
| [Somatic hypermutation of immunoglobulin genes](https://reactome.org/content/detail/R-HSA-9938024) | electronic |

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

**Molecular function:** identical protein binding, protein homodimerization activity.

**Biological process:** endosomal transport, transcription initiation-coupled chromatin remodeling.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-20.

**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 | 2025-11-20 |

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

## Similar variants {#similar}

Related DPY30 variant pages (same residue, condition, or type): [DPY30 p.Ala85Val](/variant/dpy30-p-ala85val), [DPY30 p.Arg98Gln](/variant/dpy30-p-arg98gln), [DPY30 p.Phe95Ser](/variant/dpy30-p-phe95ser), [DPY30 p.Val31Leu](/variant/dpy30-p-val31leu).

### 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 4662050). 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.*