Is DROSHA p.Arg1066Cys (c.3196C>T) pathogenic?

DROSHA p.Arg1066Cys (c.3196C>T) is classified Uncertain significance in DROSHA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-25). AlphaMissense: likely benign (0.2753); Very rare (popmax 0.0067%, eas).

How common is DROSHA p.Arg1066Cys (c.3196C>T) in the general population?

DROSHA p.Arg1066Cys (c.3196C>T) is very rare (popmax 0.0067%, eas) (gnomAD).

What do computational predictors say about DROSHA p.Arg1066Cys (c.3196C>T)?

AlphaMissense predicts likely benign (score 0.2753) — an in-silico prediction, not a clinical call.

DROSHA p.Arg1066Cys

c.3196C>T · rs370990538 · VCV2614056

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2753 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0067%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2753	likely benign
REVEL	0.724	pathogenic-leaning
SaProt	LLR -9.04	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 8,754 bp · p 0.013 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0067% East Asian · 3/44,788 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.00186% 30/1,611,352 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0067%	14,929
African / African-American	0.00401%	24,930
South Asian	0.00331%	30,220
Admixed American	0.00167%	59,860
European (non-Finnish)	0.00161%	62,027
Remaining individualsnot grpmax-eligible	0.0016%	62,340

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.Arg1066Cys
Coding: c.3196C>T
MANE Select: NM_001382508
dbSNP: rs370990538
Type: single nucleotide variant
Location: chr5:31429495 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.94 · 12 PDB
Residue 1066: 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

Similar variants

DROSHA p.Arg234Ter Uncertain significance ★★ same type
DROSHA p.Asp248His Uncertain significance ★★ ⚠ same type
DROSHA p.Lys1373Glu Uncertain significance ★★ ⚠ same type
DROSHA p.Pro100Leu Uncertain significance ★★ ⚠ same type
DROSHA c.3216+9A>G Benign ★★ same type
DROSHA p.Ile1309= Benign ★★ same type
DROSHA p.Leu1009= Benign ★★ same type
DROSHA p.Lys388= Benign ★★ same type

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-arg1066cys (accessed [today's date]).

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