# NM_001382508.1(DROSHA):c.56C>G (p.Pro19Arg)

https://sugi.bio/variant/drosha-p-pro19arg

## Summary

**DROSHA p.Pro19Arg (c.56C>G)** is classified **Uncertain significance** in DROSHA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-06-10). AlphaMissense: likely benign (0.325); Absent from gnomAD v4.1; Associated with DROSHA-related disorder.

**At a glance:** Uncertain significance · review: No assertion criteria · 1 submitter · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DROSHA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to DROSHA-related disorder.

*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 | [DROSHA](https://sugi.bio/atlas/gene/DROSHA/) |
| Protein change (HGVS p.) | p.Pro19Arg |
| Coding change (HGVS c.) | c.56C>G |
| MANE Select transcript | [NM_001382508](https://www.ncbi.nlm.nih.gov/nuccore/NM_001382508) |
| Variant type | single nucleotide variant |
| Location | chr5:31526877-31526877 (GRCh38) |
| ClinVar | [VCV3347556](https://www.ncbi.nlm.nih.gov/clinvar/variation/3347556/) |

**All HGVS expressions:** `NC_000005.10:g.31526877G>C`, `NC_000005.9:g.31526984G>C`, `NG_051574.1:g.10299C>G`, `NM_001100412.2:c.56C>G`, `NM_001382508.1:c.56C>G`, `NM_013235.5:c.56C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.325)
- REVEL 0.144 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.181 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 11.731, GERP 1.27, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.3**. 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 1.00** across the covering region of the MANE Select transcript (31,515,047–31,529,059), spanning 14,012 bp. Chi-square p 0.98. 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}

**DROSHA** population constraint: LOEUF 0.39, pLI 1, missense-Z 4.5499. *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 **19** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 70.94, 40% of residues very-high.

**12 experimental structure(s)** (PDB): [2KHX](https://www.rcsb.org/structure/2KHX), [2NA2](https://www.rcsb.org/structure/2NA2), [5B16](https://www.rcsb.org/structure/5B16), [6LXD](https://www.rcsb.org/structure/6LXD), [6LXE](https://www.rcsb.org/structure/6LXE), [6V5B](https://www.rcsb.org/structure/6V5B) — incl. mutant structure 2NA2.

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

*Describes the biological roles of DROSHA (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:** DROSHA's established molecular role includes lipopolysaccharide binding. p.Pro19Arg falls in the disordered region.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [MicroRNA (miRNA) biogenesis](https://reactome.org/content/detail/R-HSA-203927) | curated |

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

**Molecular function:** lipopolysaccharide binding, RNA binding, ribonuclease III activity, DEAD/H-box RNA helicase binding, protein homodimerization activity, SMAD binding.

**Biological process:** primary miRNA processing, defense response to Gram-negative bacterium, defense response to Gram-positive bacterium.

## Clinical significance {#significance}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-06-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-06-10 |

## Associated conditions {#conditions}

[DROSHA-related disorder](https://sugi.bio/atlas/disease/drosha-related-disorder/).

**Reported phenotype names (ClinVar):** DROSHA-related disorder, DROSHA-related condition.

## Similar variants {#similar}

Related DROSHA variant pages (same residue, condition, or type): [DROSHA p.Arg234Ter](/variant/drosha-p-arg234ter), [DROSHA p.Asp248His](/variant/drosha-p-asp248his), [DROSHA p.Pro100Leu](/variant/drosha-p-pro100leu), [DROSHA p.Arg287Ter](/variant/drosha-p-arg287ter), [DROSHA p.Arg354Cys](/variant/drosha-p-arg354cys), [DROSHA p.Arg40Thr](/variant/drosha-p-arg40thr), [DROSHA p.Asp1219Gly](/variant/drosha-p-asp1219gly), [DROSHA p.Pro211Thr](/variant/drosha-p-pro211thr).

### 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 3347556). 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.*