Is DROSHA p.Arg354= (c.1062C>T) pathogenic?

DROSHA p.Arg354= (c.1062C>T) is classified Likely benign in DROSHA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-10-18). Very rare (popmax 0.0051%, amr); Associated with DROSHA-related disorder.

What condition is associated with DROSHA p.Arg354= (c.1062C>T)?

DROSHA p.Arg354= (c.1062C>T) is associated with DROSHA-related disorder (ClinVar).

How common is DROSHA p.Arg354= (c.1062C>T) in the general population?

DROSHA p.Arg354= (c.1062C>T) is very rare (popmax 0.0051%, amr) (gnomAD).

DROSHA p.Arg354=

c.1062C>T · rs779032953 · VCV3047915

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0051%, amr)

Conditions

DROSHA-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.061	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.21	GERP -3.2, phastCons 0.009
Overall
CADD	7.308	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0051% Admixed American · 3/58,826 alleles

Filtering AF 0.00135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000675%

Overall 0.000206% 3/1,456,620 alleles · very rare

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.Arg354=
Coding: c.1062C>T
MANE Select: NM_001382508
dbSNP: rs779032953
Type: single nucleotide variant
Location: chr5:31515216 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.94 · 12 PDB
Residue 354: the 'disordered' region

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

Disease context

DROSHA-related disorder

Similar variants

DROSHA p.Arg354Cys 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.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-arg354 (accessed [today's date]).

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