Is DROSHA p.Leu917= (c.2749T>C) pathogenic?

DROSHA p.Leu917= (c.2749T>C) is classified Likely benign in DROSHA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-12-15). Absent from gnomAD v4.1; Associated with DROSHA-related disorder.

What condition is associated with DROSHA p.Leu917= (c.2749T>C)?

DROSHA p.Leu917= (c.2749T>C) is associated with DROSHA-related disorder (ClinVar).

How common is DROSHA p.Leu917= (c.2749T>C) in the general population?

DROSHA p.Leu917= (c.2749T>C) is absent from gnomAD v4.1 (gnomAD).

DROSHA p.Leu917=

c.2749T>C · rs2478027029 · VCV3045762

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

DROSHA-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 0.53, phastCons 0.057
Overall
CADD	5.113	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DROSHA
Protein: p.Leu917=
Coding: c.2749T>C
MANE Select: NM_001382508
dbSNP: rs2478027029
Type: single nucleotide variant
Location: chr5:31449353 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.94 · 12 PDB
Residue 917: the rnase iii 1 domain; an α-helix; the 'necessary for interaction with dgcr8 and pri-mirna processing activity' region

Full DROSHA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

DROSHA-related disorder

Similar variants

DROSHA p.Leu917Ser Uncertain significance ★ ⚠ same residue
DROSHA p.Arg234Ter Uncertain significance ★★ same condition
DROSHA p.Asp248His Uncertain significance ★★ ⚠ same condition
DROSHA p.Pro100Leu Uncertain significance ★★ ⚠ same condition
DROSHA p.Arg287Ter Uncertain significance ★ same condition
DROSHA p.Arg354Cys Uncertain significance ★ ⚠ same condition
DROSHA p.Arg40Thr Uncertain significance ★ ⚠ same condition
DROSHA p.Asp1219Gly Uncertain significance ★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/drosha-p-leu917 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown