Is DROSHA p.Pro83Leu (c.248C>T) pathogenic?

DROSHA p.Pro83Leu (c.248C>T) is classified Likely benign in DROSHA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.1643); Rare (popmax 0.796%, nfe).

How common is DROSHA p.Pro83Leu (c.248C>T) in the general population?

DROSHA p.Pro83Leu (c.248C>T) is rare (popmax 0.796%, nfe) (gnomAD).

What do computational predictors say about DROSHA p.Pro83Leu (c.248C>T)?

AlphaMissense predicts likely benign (score 0.1643) — an in-silico prediction, not a clinical call.

DROSHA p.Pro83Leu

c.248C>T · rs149389256 · VCV791420

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1643 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.796%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1643	likely benign
REVEL	0.325	indeterminate
SaProt	LLR -9.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 14 kb · p 0.98 · regional, not allelic
Overall
CADD	26.0	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 0.796% European (non-Finnish) · 9,055/1,136,884 alleles

Filtering AF 0.783% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.777%

Overall 0.634% 9,657/1,522,190 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.796%	126
Remaining individualsnot grpmax-eligible	0.465%	215
Finnishnot grpmax-eligible	0.271%	369
African / African-American	0.141%	710
Admixed American	0.129%	774
Middle Eastern	0.0358%	2,796
Ashkenazi Jewishnot grpmax-eligible	0.00844%	11,854
South Asian	0.00264%	37,847
East Asian	0.00228%	43,876

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.Pro83Leu
Coding: c.248C>T
MANE Select: NM_001382508
dbSNP: rs149389256
Type: single nucleotide variant
Location: chr5:31526685 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.94 · 12 PDB
Residue 83: the 'disordered' region

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

Similar variants

DROSHA p.Pro83Arg Uncertain significance ⚠ same residue
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

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-pro83leu (accessed [today's date]).

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