Is DROSHA p.Pro1261Ser (c.3781C>T) pathogenic?

DROSHA p.Pro1261Ser (c.3781C>T) is classified Uncertain significance in DROSHA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-17). AlphaMissense: likely pathogenic (0.9887); Very rare (popmax 0.0011%, sas).

How common is DROSHA p.Pro1261Ser (c.3781C>T) in the general population?

DROSHA p.Pro1261Ser (c.3781C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about DROSHA p.Pro1261Ser (c.3781C>T)?

AlphaMissense predicts likely pathogenic (score 0.9887) — an in-silico prediction, not a clinical call.

DROSHA p.Pro1261Ser

c.3781C>T · rs770406706 · VCV2307774

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9887 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9887	likely pathogenic
REVEL	0.794	moderately pathogenic-leaning
SaProt	LLR -12.33	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 7,746 bp · p 5.9e-12 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,068 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00031% 5/1,613,702 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,454
South Asiangrpmax	0.0011%	91,068
European (non-Finnish)	0.000254%	393,278

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1261Ser
Coding: c.3781C>T
MANE Select: NM_001382508
dbSNP: rs770406706
Type: single nucleotide variant
Location: chr5:31409129 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.94 · 12 PDB
Residue 1261: 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

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-pro1261ser (accessed [today's date]).

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