Is DROSHA p.Cys1269= (c.3807C>T) pathogenic?

DROSHA p.Cys1269= (c.3807C>T) is classified Likely benign in DROSHA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-07-05). Rare (popmax 0.394%, eas); Associated with DROSHA-related disorder.

What condition is associated with DROSHA p.Cys1269= (c.3807C>T)?

DROSHA p.Cys1269= (c.3807C>T) is associated with DROSHA-related disorder (ClinVar).

How common is DROSHA p.Cys1269= (c.3807C>T) in the general population?

DROSHA p.Cys1269= (c.3807C>T) is rare (popmax 0.394%, eas) (gnomAD).

DROSHA p.Cys1269=

c.3807C>T · rs181677016 · VCV3040208

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.394%, eas)

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 1.1	GERP -2.9, phastCons 0.6
Overall
CADD	6.233	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.394% East Asian · 177/44,870 alleles

Filtering AF 0.347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.329%

Overall 0.0157% 254/1,613,914 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.394%	254
South Asian	0.0494%	2,024
Finnishnot grpmax-eligible	0.0234%	4,267
Remaining individualsnot grpmax-eligible	0.0144%	6,943
Admixed American	0.00167%	60,020
European (non-Finnish)	0.000593%	168,546

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.Cys1269=
Coding: c.3807C>T
MANE Select: NM_001382508
dbSNP: rs181677016
Type: single nucleotide variant
Location: chr5:31409103 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.94 · 12 PDB
Residue 1269: an α-helix; the drbm 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-cys1269 (accessed [today's date]).

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