Is DROSHA p.Val1004= (c.3012T>A) pathogenic?

DROSHA p.Val1004= (c.3012T>A) is classified Likely benign in DROSHA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-03-04). Very rare (popmax 0.00934%, afr); Associated with DROSHA-related disorder.

What condition is associated with DROSHA p.Val1004= (c.3012T>A)?

DROSHA p.Val1004= (c.3012T>A) is associated with DROSHA-related disorder (ClinVar).

How common is DROSHA p.Val1004= (c.3012T>A) in the general population?

DROSHA p.Val1004= (c.3012T>A) is very rare (popmax 0.00934%, afr) (gnomAD).

DROSHA p.Val1004=

c.3012T>A · rs909060563 · VCV3060332

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

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 0.56	GERP -3.8, phastCons 0.87
Overall
CADD	6.638	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00934% African / African-American · 7/74,922 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000434% 7/1,613,836 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.Val1004=
Coding: c.3012T>A
MANE Select: NM_001382508
dbSNP: rs909060563
Type: single nucleotide variant
Location: chr5:31435795 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.94 · 12 PDB
Residue 1004: the rnase iii 1 domain; 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-val1004 (accessed [today's date]).

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