Is SGCE p.Pro399Leu (c.1196C>T) pathogenic?

SGCE p.Pro399Leu (c.1196C>T) is classified Conflicting classifications of pathogenicity in SGCE (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-27). AlphaMissense: likely benign (0.1929); Ultra-rare (popmax 0.0143%, nfe); Associated with myoclonic dystonia 11.

What condition is associated with SGCE p.Pro399Leu (c.1196C>T)?

SGCE p.Pro399Leu (c.1196C>T) is associated with myoclonic dystonia 11 (ClinVar).

How common is SGCE p.Pro399Leu (c.1196C>T) in the general population?

SGCE p.Pro399Leu (c.1196C>T) is ultra-rare (popmax 0.0143%, nfe) (gnomAD).

How is Myoclonus-dystonia syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SGCE p.Pro399Leu (c.1196C>T)?

AlphaMissense predicts likely benign (score 0.1929) — an in-silico prediction, not a clinical call.

SGCE p.Pro399Leu

c.1196C>T · rs17851923 · VCV532793

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1929 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myoclonic dystonia 11

Computational evidence

Protein change
AlphaMissense	0.1929	likely benign
REVEL	0.796	moderately pathogenic-leaning
SaProt	LLR -7.92	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 71 kb · p 0.00058 · regional, not allelic
Overall
CADD	24.8	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 0.0143% European (non-Finnish) · 169/1,179,278 alleles

Filtering AF 0.0125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.0114% 184/1,613,164 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0143%	6,978
Remaining individualsnot grpmax-eligible	0.0128%	7,808
African / African-American	0.00668%	14,978
Admixed American	0.00333%	29,992

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: SGCE
Protein: p.Pro399Leu
Coding: c.1196C>T
MANE Select: NM_022900 · reported on NM_003919
dbSNP: rs17851923
Type: single nucleotide variant
Location: chr7:94598832 (GRCh38)

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

Disease context

myoclonic dystonia 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Myoclonus-dystonia syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

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/sgce-p-pro399leu (accessed [today's date]).

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