Is DROSHA p.Arg279Cys (c.835C>T) pathogenic?

DROSHA p.Arg279Cys (c.835C>T) is classified Uncertain significance in DROSHA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-07-25). AlphaMissense: ambiguous (0.3468); Rare (popmax 0.158%, nfe); Associated with DROSHA-related disorder.

What condition is associated with DROSHA p.Arg279Cys (c.835C>T)?

DROSHA p.Arg279Cys (c.835C>T) is associated with DROSHA-related disorder (ClinVar).

How common is DROSHA p.Arg279Cys (c.835C>T) in the general population?

DROSHA p.Arg279Cys (c.835C>T) is rare (popmax 0.158%, nfe) (gnomAD).

What do computational predictors say about DROSHA p.Arg279Cys (c.835C>T)?

AlphaMissense predicts ambiguous (score 0.3468) — an in-silico prediction, not a clinical call.

DROSHA p.Arg279Cys

c.835C>T · rs201276010 · VCV2636854

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3468 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.158%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

DROSHA-related disorder

Computational evidence

Protein change
AlphaMissense	0.3468	ambiguous
REVEL	0.226	benign-leaning
SaProt	LLR -10.82	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 0.43, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 14 kb · p 0.98 · regional, not allelic
Overall
CADD	26.5	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 0.158% European (non-Finnish) · 1,837/1,165,992 alleles

Filtering AF 0.152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.149%

Overall 0.12% 1,907/1,595,804 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.158%	635
Remaining individualsnot grpmax-eligible	0.0617%	1,620
African / African-American	0.0268%	3,732
Finnishnot grpmax-eligible	0.00942%	10,621
Admixed American	0.00673%	14,853
South Asian	0.00222%	45,026

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.Arg279Cys
Coding: c.835C>T
MANE Select: NM_001382508
dbSNP: rs201276010
Type: single nucleotide variant
Location: chr5:31526098 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.94 · 12 PDB
Residue 279: 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.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-arg279cys (accessed [today's date]).

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