Is DROSHA p.Phe63Leu (c.187T>C) pathogenic?

DROSHA p.Phe63Leu (c.187T>C) is classified Uncertain significance in DROSHA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-08). AlphaMissense: ambiguous (0.4642); Ultra-rare (popmax 0.0167%, amr).

How common is DROSHA p.Phe63Leu (c.187T>C) in the general population?

DROSHA p.Phe63Leu (c.187T>C) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about DROSHA p.Phe63Leu (c.187T>C)?

AlphaMissense predicts ambiguous (score 0.4642) — an in-silico prediction, not a clinical call.

DROSHA p.Phe63Leu

c.187T>C · VCV4662179

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4642 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4642	ambiguous
REVEL	0.082	moderately benign-leaning
SaProt	LLR -6.78	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 14 kb · p 0.98 · regional, not allelic
Overall
CADD	23.5	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 0.0167% Admixed American · 9/53,772 alleles

Filtering AF 0.00864% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00647%

Overall 0.00139% 22/1,585,038 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,975
Remaining individualsnot grpmax-eligible	0.00327%	30,569
European (non-Finnish)	0.000942%	106,178

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.Phe63Leu
Coding: c.187T>C
MANE Select: NM_001382508
Type: single nucleotide variant
Location: chr5:31526746 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.94 · 12 PDB
Residue 63: the 'disordered' 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-phe63leu (accessed [today's date]).

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