# NM_003919.3(SGCE):c.1195C>T (p.Pro399Ser)

https://sugi.bio/variant/sgce-p-pro399ser

## Summary

**SGCE p.Pro399Ser (c.1195C>T)** is classified **Uncertain significance** in SGCE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-03). AlphaMissense: likely benign (0.1193); Very rare (popmax 0.000509%, nfe); Associated with myoclonic dystonia 11.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs747427574 · 3 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000509%, nfe)

> **Built without this gene's context.** ClinVar files this variant under an overlapping gene, so its own gene's record set does not contain it and this page is assembled from the variant alone. Gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up — absent from this page, not from the data.

## For patients & families {#patients}

This is a change in the SGCE gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to myoclonic dystonia 11.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Not applicable |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Commonly reported features of Myoclonus-dystonia syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Dystonia — Very frequent (99-80%)
- Myoclonus — Very frequent (99-80%)
- Spinal myoclonus — Very frequent (99-80%)
- Limb myoclonus — Very frequent (99-80%)
- Torticollis — Frequent (79-30%)
- Depression — Frequent (79-30%)
- Compulsive behaviors — Frequent (79-30%)
- Anxiety — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018616/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SGCE](https://sugi.bio/atlas/gene/SGCE/) |
| Protein change (HGVS p.) | p.Pro399Ser |
| Coding change (HGVS c.) | c.1195C>T |
| MANE Select transcript | [NM_003919](https://www.ncbi.nlm.nih.gov/nuccore/NM_003919) |
| dbSNP | [rs747427574](https://www.ncbi.nlm.nih.gov/snp/rs747427574/) |
| Variant type | single nucleotide variant |
| Location | chr7:94598833-94598833 (GRCh38) |
| ClinVar | [VCV2045520](https://www.ncbi.nlm.nih.gov/clinvar/variation/2045520/) |

**All HGVS expressions:** `LRG_206:g.62740C>T`, `LRG_206t1:c.1195C>T`, `NC_000007.13:g.94228145G>A`, `NC_000007.14:g.94598833G>A`, `NG_008893.3:g.62740C>T`, `NM_001099400.2:c.1168C>T`, `NM_001099401.2:c.1195C>T`, `NM_001301139.2:c.1072C>T`, `NM_001346713.2:c.1303C>T`, `NM_001346715.2:c.1276C>T`, `NM_001346717.2:c.1168C>T`, `NM_001346719.2:c.1108C>T`, `NM_001346720.2:c.922C>T`, `NM_001362807.2:c.1081C>T`, `NM_001362808.2:c.895C>T`, `NM_001362809.2:c.1045C>T`, `NM_003919.2:c.1195C>T`, `NM_003919.3:c.1195C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1193)
- REVEL 0.681 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -6.794 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 9.946, GERP 1.72, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.2**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.85** across the covering region of the MANE Select transcript (94,585,502–94,656,098), spanning 70,596 bp. Chi-square p 0.00058. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.000509%** (nfe) · FAF95 0.000183% · FAF99 0.00012% · 6/1,179,194 in the highest group · 6/1,613,200 alleles overall — very rare (popmax 0.000509%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-03-03.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2025–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-05 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-03-03 |

## Associated conditions {#conditions}

[myoclonic dystonia 11](https://sugi.bio/atlas/disease/myoclonic-dystonia-11/).

**Reported phenotype names (ClinVar):** Myoclonic dystonia 11, Inborn genetic diseases, not specified, AllHighlyPenetrant, DYT-SGCE, Myoclonic dystonia, Dystonia 11, Dystonia, alcohol responsive, Hereditary essential myoclonus, SGCE Myoclonus-Dystonia.

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2045520). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*