Is DROSHA p.Leu1057= (c.3169C>T) pathogenic?

DROSHA p.Leu1057= (c.3169C>T) is classified Likely benign in DROSHA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-08-04). Rare (popmax 0.182%, amr); Associated with DROSHA-related disorder.

What condition is associated with DROSHA p.Leu1057= (c.3169C>T)?

DROSHA p.Leu1057= (c.3169C>T) is associated with DROSHA-related disorder (ClinVar).

How common is DROSHA p.Leu1057= (c.3169C>T) in the general population?

DROSHA p.Leu1057= (c.3169C>T) is rare (popmax 0.182%, amr) (gnomAD).

DROSHA p.Leu1057=

c.3169C>T · rs61751195 · VCV3041551

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.182%, amr)

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 7.6	GERP 1.7, phastCons 1
Overall
CADD	9.506	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.182% Admixed American · 109/59,926 alleles

Filtering AF 0.154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.144%

Overall 0.0968% 1,561/1,611,966 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.196%	509
Admixed Americangrpmax	0.182%	550
European (non-Finnish)	0.112%	896
Remaining individualsnot grpmax-eligible	0.0978%	1,023
Middle Eastern	0.033%	3,027
African / African-American	0.02%	4,999

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. 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.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DROSHA
Protein: p.Leu1057=
Coding: c.3169C>T
MANE Select: NM_001382508
dbSNP: rs61751195
Type: single nucleotide variant
Location: chr5:31429522 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.94 · 12 PDB
Residue 1057: 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.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
DROSHA p.Pro211Thr 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-leu1057 (accessed [today's date]).

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