Is DROSHA p.Ala557Ser (c.1669G>T) pathogenic?

DROSHA p.Ala557Ser (c.1669G>T) is classified Likely benign in DROSHA (ClinVar, No assertion criteria, 2 submitters; last evaluated 2020-07-03). AlphaMissense: likely benign (0.0863); Rare (popmax 0.292%, nfe); Associated with DROSHA-related disorder.

What condition is associated with DROSHA p.Ala557Ser (c.1669G>T)?

DROSHA p.Ala557Ser (c.1669G>T) is associated with DROSHA-related disorder (ClinVar).

How common is DROSHA p.Ala557Ser (c.1669G>T) in the general population?

DROSHA p.Ala557Ser (c.1669G>T) is rare (popmax 0.292%, nfe) (gnomAD).

What do computational predictors say about DROSHA p.Ala557Ser (c.1669G>T)?

AlphaMissense predicts likely benign (score 0.0863) — an in-silico prediction, not a clinical call.

DROSHA p.Ala557Ser

c.1669G>T · rs61751194 · VCV3050303

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0863 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.292%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DROSHA-related disorder

Computational evidence

Protein change
AlphaMissense	0.0863	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -4.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 0.69, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 83 kb · p 1.4e-29 · regional, not allelic
Overall
CADD	22.6	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 0.292% European (non-Finnish) · 3,448/1,179,118 alleles

Filtering AF 0.284% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.281%

Overall 0.238% 3,840/1,611,520 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.292%	342
Remaining individualsnot grpmax-eligible	0.215%	466
Middle Eastern	0.182%	551
Finnishnot grpmax-eligible	0.13%	770
Admixed American	0.114%	877
South Asian	0.0664%	1,505
African / African-American	0.0441%	2,268
Ashkenazi Jewishnot grpmax-eligible	0.0102%	9,843

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.Ala557Ser
Coding: c.1669G>T
MANE Select: NM_001382508
dbSNP: rs61751194
Type: single nucleotide variant
Location: chr5:31495372 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.94 · 12 PDB
Residue 557: 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-ala557ser (accessed [today's date]).

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