# NM_000100.4(CSTB):c.212A>C (p.Gln71Pro)

https://sugi.bio/variant/cstb-p-gln71pro

## Summary

**CSTB p.Gln71Pro (c.212A>C)** is classified **Pathogenic** in CSTB (ClinVar, No assertion criteria, 2 submitters; last evaluated 2005-02-01). AlphaMissense: likely pathogenic (0.571); Absent from gnomAD v4.1; Associated with Unverricht-Lundborg syndrome.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs121909346 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CSTB gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to Unverricht-Lundborg syndrome.

*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 recessive |
| Age of onset (of this condition) | Adolescent, Childhood |
| Prevalence | 1-9 / 100 000 (Finland) |
| Clinical trials | 5 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CSTB is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Progressive myoclonic epilepsy type 1** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Myoclonus — Very frequent (99-80%)
- Limb ataxia — Very frequent (99-80%)
- EEG with polyspike wave complexes — Very frequent (99-80%)
- Morning myoclonic jerks — Very frequent (99-80%)
- Ataxia — Frequent (79-30%)
- Dysarthria — Frequent (79-30%)
- Intention tremor — Frequent (79-30%)
- Dementia — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003876/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CSTB](https://sugi.bio/atlas/gene/CSTB/) |
| Protein change (HGVS p.) | p.Gln71Pro |
| Coding change (HGVS c.) | c.212A>C |
| MANE Select transcript | [NM_000100](https://www.ncbi.nlm.nih.gov/nuccore/NM_000100) |
| dbSNP | [rs121909346](https://www.ncbi.nlm.nih.gov/snp/rs121909346/) |
| Variant type | single nucleotide variant |
| Location | chr21:43774287-43774287 (GRCh38) |
| ClinVar | [VCV8400](https://www.ncbi.nlm.nih.gov/clinvar/variation/8400/) |

**All HGVS expressions:** `LRG_485:g.7092A>C`, `NC_000021.8:g.45194168T>G`, `NC_000021.9:g.43774287T>G`, `NG_011545.1:g.7092A>C`, `NM_000100.4:c.212A>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.571) — concordant with the pathogenic call
- REVEL 0.484 (indeterminate)
- SaProt LLR -15 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP -0.547, GERP -3.28 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 11.4**. 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 0.98** across the covering region of the MANE Select transcript (43,774,205–43,776,269), spanning 2,064 bp. Chi-square p 0.83. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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.*

## Gene constraint & dosage {#gene-context}

**CSTB** population constraint: LOEUF 1.681, pLI 0.0029059, missense-Z -0.24896; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Unverricht-Lundborg syndrome** — Definitive (AR)
- **genetic developmental and epileptic encephalopathy** — Moderate (AR)

## Protein context {#protein}

Residue **71** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 95.81, 96% of residues very-high.

**3 experimental structure(s)** (PDB): [1STF](https://www.rcsb.org/structure/1STF), [2OCT](https://www.rcsb.org/structure/2OCT), [4N6V](https://www.rcsb.org/structure/4N6V).

## What this gene does {#gene-function}

*Describes the biological roles of CSTB (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CSTB's established molecular role includes protease binding.


### Pathways affected {#pathways}

CSTB participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protease binding, RNA binding, endopeptidase inhibitor activity, cysteine-type endopeptidase inhibitor activity.

**Biological process:** negative regulation of proteolysis.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2005-02-01.

**Submitter consensus:** conflicting (1 not provided, 1 Pathogenic).

**Submission history:** 2 submissions (2005); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneReviews | not provided | no classification provided | literature only |  |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2005-02-01 |

## Associated conditions {#conditions}

[Unverricht-Lundborg syndrome](https://sugi.bio/atlas/disease/unverricht-lundborg-syndrome/).

**Reported phenotype names (ClinVar):** Unverricht-Lundborg syndrome, Myoclonic epilepsy of unverricht and lundborg, Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), Progressive myoclonus epilepsy baltic myoclonic epilepsy, Myoclonus progressive epilepsy of Unverricht and Lundborg, Unverricht-Lundborg Disease, EPILEPSY, PROGRESSIVE MYOCLONIC, 1A.

## Similar variants {#similar}

Related CSTB variant pages (same residue, condition, or type): [CSTB p.Gln71=](/variant/cstb-p-gln71), [CSTB c.67-1G>C](/variant/cstb-c-67-minus-1g-c), [CSTB p.Arg68Ter](/variant/cstb-p-arg68ter), [CSTB p.Gln22Ter](/variant/cstb-p-gln22ter), [CSTB p.Gln46Ter](/variant/cstb-p-gln46ter), [CSTB p.Tyr53Cys](/variant/cstb-p-tyr53cys), [CSTB p.Val57Leu](/variant/cstb-p-val57leu), [CSTB c.67-3T>C](/variant/cstb-c-67-minus-3t-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 8400). 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.*