Is DROSHA p.Ser321Leu (c.962C>T) pathogenic?

DROSHA p.Ser321Leu (c.962C>T) is classified Benign in DROSHA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-30). AlphaMissense: likely benign (0.08); Common (popmax 49.6%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with DROSHA-related disorder.

What condition is associated with DROSHA p.Ser321Leu (c.962C>T)?

DROSHA p.Ser321Leu (c.962C>T) is associated with DROSHA-related disorder (ClinVar).

What do computational predictors say about DROSHA p.Ser321Leu (c.962C>T)?

AlphaMissense predicts likely benign (score 0.08) — an in-silico prediction, not a clinical call.

DROSHA p.Ser321Leu

Q: How common is DROSHA p.Ser321Leu (c.962C>T) in the general population?

DROSHA p.Ser321Leu (c.962C>T) is common (popmax 49.6%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.962C>T · rs55656741 · VCV3059023

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.08 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 49.6%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DROSHA-related disorder

Computational evidence

Protein change
AlphaMissense	0.08	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -7.17	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 1.3	GERP 1.4, phastCons 0.84
Regional constraint	o/e 1.00	unconstrained · MANE · 14 kb · p 0.98 · regional, not allelic
Overall
CADD	17.84	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 49.6% European (non-Finnish) · 567,717/1,144,472 alleles

Filtering AF 49.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 49.5%

Overall 46% 712,000/1,548,624 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	52%	2
European (non-Finnish)grpmax	49.6%	2
South Asian	47.8%	2
Finnishnot grpmax-eligible	47.1%	2
Remaining individualsnot grpmax-eligible	43.2%	2
Admixed American	42.4%	2
Ashkenazi Jewishnot grpmax-eligible	40.6%	2
Middle Eastern	37.3%	3
East Asian	19.1%	5
African / African-American	8.77%	11

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser321Leu
Coding: c.962C>T
MANE Select: NM_001382508
dbSNP: rs55656741
Type: single nucleotide variant
Location: chr5:31515550 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.94 · 12 PDB
Residue 321: a UniProt-annotated variant site (in); the 'disordered' 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-ser321leu (accessed [today's date]).

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