Is SGCE p.Pro4Leu (c.11C>T) pathogenic?

SGCE p.Pro4Leu (c.11C>T) is classified Uncertain significance in SGCE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). AlphaMissense: likely benign (0.2356); Ultra-rare (popmax 0.0117%, amr); Associated with myoclonic dystonia 11.

What condition is associated with SGCE p.Pro4Leu (c.11C>T)?

SGCE p.Pro4Leu (c.11C>T) is associated with myoclonic dystonia 11 (ClinVar).

How common is SGCE p.Pro4Leu (c.11C>T) in the general population?

SGCE p.Pro4Leu (c.11C>T) is ultra-rare (popmax 0.0117%, amr) (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.Pro4Leu (c.11C>T)?

AlphaMissense predicts likely benign (score 0.2356) — an in-silico prediction, not a clinical call.

SGCE p.Pro4Leu

c.11C>T · rs372207991 · VCV1054774

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2356 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

myoclonic dystonia 11

Computational evidence

Protein change
AlphaMissense	0.2356	likely benign
REVEL	0.473	indeterminate
SaProt	LLR -5.87	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 5.9	GERP 1.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 71 kb · p 0.00058 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/59,982 alleles

Filtering AF 0.00544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000684% 11/1,607,738 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,569
East Asian	0.00223%	44,818
Remaining individualsnot grpmax-eligible	0.00161%	62,290
South Asian	0.0011%	90,942
European (non-Finnish)	8.51e-05%	1,174,466

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.Pro4Leu
Coding: c.11C>T
MANE Select: NM_003919
dbSNP: rs372207991
Type: single nucleotide variant
Location: chr7:94656088 (GRCh38)
Gene constraint: LOEUF 0.628 · pLI 0.32 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.19

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)

Similar variants

SGCE p.Pro4Ser Uncertain significance ★★ ⚠ same residue
SGCE p.Pro4= Likely benign ★ same residue
SGCE c.109+1G>A Pathogenic ★★ same condition
SGCE c.109+2T>C Pathogenic ★★ same condition
SGCE p.Arg23Cys Uncertain significance ★★ ⚠ same condition
SGCE p.Gly19Ser Uncertain significance ★★ ⚠ same condition
SGCE p.Ile199Met Uncertain significance ★★ same condition
SGCE p.Thr32Ala 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/sgce-p-pro4leu (accessed [today's date]).

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