Is DROSHA p.Pro67Thr (c.199C>A) pathogenic?

DROSHA p.Pro67Thr (c.199C>A) is classified Benign in DROSHA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-01-03). AlphaMissense: likely benign (0.0568); Low-frequency (popmax 2.93%, afr).

How common is DROSHA p.Pro67Thr (c.199C>A) in the general population?

DROSHA p.Pro67Thr (c.199C>A) is low-frequency (popmax 2.93%, afr) (gnomAD).

What do computational predictors say about DROSHA p.Pro67Thr (c.199C>A)?

AlphaMissense predicts likely benign (score 0.0568) — an in-silico prediction, not a clinical call.

DROSHA p.Pro67Thr

c.199C>A · rs35342496 · VCV785118

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0568 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.93%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0568	likely benign
REVEL	0.021	moderately benign-leaning
SaProt	LLR -6.73	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 8.5	GERP 1.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 14 kb · p 0.98 · regional, not allelic
Overall
CADD	23.2	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 2.93% African / African-American · 2,146/73,306 alleles

Filtering AF 2.82% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.78%

Overall 0.157% 2,483/1,578,248 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.93%	34
Admixed American	0.211%	474
Remaining individualsnot grpmax-eligible	0.199%	503
Middle Eastern	0.189%	529
European (non-Finnish)	0.00764%	13,087
South Asian	0.0047%	21,270

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.Pro67Thr
Coding: c.199C>A
MANE Select: NM_001382508
dbSNP: rs35342496
Type: single nucleotide variant
Location: chr5:31526734 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.94 · 12 PDB
Residue 67: a UniProt-annotated variant site (in); 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-pro67thr (accessed [today's date]).

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