Is DROSHA p.Ser981= (c.2943C>T) pathogenic?

DROSHA p.Ser981= (c.2943C>T) is classified Benign in DROSHA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-11-13). Low-frequency (popmax 1.68%, sas); Associated with DROSHA-related disorder.

What condition is associated with DROSHA p.Ser981= (c.2943C>T)?

DROSHA p.Ser981= (c.2943C>T) is associated with DROSHA-related disorder (ClinVar).

How common is DROSHA p.Ser981= (c.2943C>T) in the general population?

DROSHA p.Ser981= (c.2943C>T) is low-frequency (popmax 1.68%, sas) (gnomAD).

DROSHA p.Ser981=

c.2943C>T · rs17485810 · VCV3038764

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

low-frequency (popmax 1.68%, sas)

Conditions

DROSHA-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1	GERP -2.3, phastCons 0.99
Overall
CADD	13.15	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.68% South Asian · 1,487/88,492 alleles

Filtering AF 1.61% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.58%

Overall 0.265% 4,241/1,602,326 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.68%	60
Middle Eastern	0.619%	162
Remaining individualsnot grpmax-eligible	0.287%	348
Ashkenazi Jewishnot grpmax-eligible	0.24%	417
European (non-Finnish)	0.203%	492
African / African-American	0.0488%	2,051
Admixed American	0.0349%	2,866
Finnishnot grpmax-eligible	0.0347%	2,882
East Asian	0.00447%	22,383

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.Ser981=
Coding: c.2943C>T
MANE Select: NM_001382508
dbSNP: rs17485810
Type: single nucleotide variant
Location: chr5:31435864 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.94 · 12 PDB
Residue 981: the rnase iii 1 domain; 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

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-ser981 (accessed [today's date]).

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