Is DROSHA p.Arg252Gln (c.755G>A) pathogenic?

DROSHA p.Arg252Gln (c.755G>A) is classified Benign in DROSHA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2014-10-31). AlphaMissense: ambiguous (0.3904); Very rare (popmax 0.00223%, eas); Associated with Abnormality of neuronal migration.

What condition is associated with DROSHA p.Arg252Gln (c.755G>A)?

DROSHA p.Arg252Gln (c.755G>A) is associated with Abnormality of neuronal migration (ClinVar).

How common is DROSHA p.Arg252Gln (c.755G>A) in the general population?

DROSHA p.Arg252Gln (c.755G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about DROSHA p.Arg252Gln (c.755G>A)?

AlphaMissense predicts ambiguous (score 0.3904) — an in-silico prediction, not a clinical call.

DROSHA p.Arg252Gln

c.755G>A · rs201151813 · VCV208874

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3904 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Abnormality of neuronal migration

Computational evidence

Protein change
AlphaMissense	0.3904	ambiguous
REVEL	0.185	benign-leaning
SaProt	LLR -10.74	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 7.5	GERP 1.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 14 kb · p 0.98 · regional, not allelic
Overall
CADD	25.7	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 0.00223% East Asian · 1/44,862 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00112% 18/1,613,692 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,862
South Asian	0.0022%	45,520
African / African-American	0.00133%	74,948
European (non-Finnish)	0.00119%	84,274

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.Arg252Gln
Coding: c.755G>A
MANE Select: NM_001382508
dbSNP: rs201151813
Type: single nucleotide variant
Location: chr5:31526178 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.94 · 12 PDB
Residue 252: the 'disordered' region

Full DROSHA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Abnormality of neuronal migration — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-arg252gln (accessed [today's date]).

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