# NM_004589.4(SCO1):c.263dup (p.Lys89fs)

https://sugi.bio/variant/sco1-p-lys89fs

## Summary

**SCO1 p.Lys89fs (c.263dup)** is classified **Pathogenic** in SCO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-11-02). Very rare (popmax 0.00122%, nfe); Associated with mitochondrial complex IV deficiency, nuclear type 1.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1176555010 · 1 submitter · 1 linked condition · very rare (popmax 0.00122%, nfe)

## For patients & families {#patients}

This is a change in the SCO1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to mitochondrial complex IV deficiency, nuclear type 1.

*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, Mitochondrial inheritance |
| Diagnostic panels | SCO1 is a diagnostic-grade gene on 11 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015158/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SCO1](https://sugi.bio/atlas/gene/SCO1/) |
| Protein change (HGVS p.) | p.Lys89fs |
| Coding change (HGVS c.) | c.263dup |
| MANE Select transcript | [NM_004589](https://www.ncbi.nlm.nih.gov/nuccore/NM_004589) |
| dbSNP | [rs1176555010](https://www.ncbi.nlm.nih.gov/snp/rs1176555010/) |
| Variant type | Duplication |
| Location | chr17:10697244-10697245 (GRCh38) |
| ClinVar | [VCV1034098](https://www.ncbi.nlm.nih.gov/clinvar/variation/1034098/) |

**All HGVS expressions:** `NC_000017.10:g.10600562dup`, `NC_000017.11:g.10697245dup`, `NG_008228.2:g.5324dup`, `NM_004589.4:c.263dup`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -0.051, GERP -1.77, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.207, pLI 1.393e-05. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 6**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 31.0**. 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.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00122%** (nfe) · FAF95 0.000706% · FAF99 0.000552% · 14/1,150,952 in the highest group · 15/1,557,106 alleles overall — very rare (popmax 0.00122%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00167% | 59,846 |
| European (non-Finnish) (grpmax) | 0.00122% | 82,211 |

Remaining individuals shows a higher raw frequency than the grpmax group. 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.

*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}

**SCO1** population constraint: LOEUF 1.207, pLI 1.393e-05, missense-Z -0.56878. *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):

- **mitochondrial disease** — Definitive (AR)

## Protein context {#protein}

Residue **89** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 77.95, 58% of residues very-high.

**10 experimental structure(s)** (PDB): [1WP0](https://www.rcsb.org/structure/1WP0), [2GGT](https://www.rcsb.org/structure/2GGT), [2GQK](https://www.rcsb.org/structure/2GQK), [2GQL](https://www.rcsb.org/structure/2GQL), [2GQM](https://www.rcsb.org/structure/2GQM), [2GT5](https://www.rcsb.org/structure/2GT5).

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

*Describes the biological roles of SCO1 (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.*


### Pathways affected {#pathways}

SCO1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Complex IV assembly](https://reactome.org/content/detail/R-HSA-9864848) | curated |

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

**Biological process:** mitochondrial respiratory chain complex IV assembly.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-11-02.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2018-11-02 |

## Associated conditions {#conditions}

[mitochondrial complex IV deficiency, nuclear type 1](https://sugi.bio/atlas/disease/mitochondrial-complex-iv-deficiency-nuclear-type-1/).

**Reported phenotype names (ClinVar):** Mitochondrial complex IV deficiency, nuclear type 1, Mitochondrial complex IV deficiency, Complex 4 mitochondrial respiratory chain deficiency, Deficiency of mitochondrial respiratory chain complex4, Complex IV deficiency, COX DEFICIENCY.

## Similar variants {#similar}

Related SCO1 variant pages (same residue, condition, or type): [SCO1 c.771+3G>C](/variant/sco1-c-771-plus-3g-c), [SCO1 p.Met1Thr](/variant/sco1-p-met1thr), [SCO1 p.Pro32Ala](/variant/sco1-p-pro32ala), [SCO1 p.Gly229Ser](/variant/sco1-p-gly229ser), [SCO1 c.*326C>T](/variant/sco1-c-star-326c-t), [SCO1 c.*526T>C](/variant/sco1-c-star-526t-c), [SCO1 c.*731A>G](/variant/sco1-c-star-731a-g), [SCO1 c.*80A>G](/variant/sco1-c-star-80a-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1034098). 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.*