# NM_018127.7(ELAC2):c.2207del (p.Ser736fs)

https://sugi.bio/variant/elac2-p-ser736fs

## Summary

**ELAC2 p.Ser736fs (c.2207del)** is classified **Pathogenic** in ELAC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-08). Very rare (popmax 8.47e-05%, nfe); Associated with combined oxidative phosphorylation defect type 17.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the ELAC2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to combined oxidative phosphorylation defect type 17.

*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) | Infancy, Neonatal |
| Diagnostic panels | ELAC2 is a diagnostic-grade gene on 12 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017589/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ELAC2](https://sugi.bio/atlas/gene/ELAC2/) |
| Protein change (HGVS p.) | p.Ser736fs |
| Coding change (HGVS c.) | c.2207del |
| MANE Select transcript | [NM_018127](https://www.ncbi.nlm.nih.gov/nuccore/NM_018127) |
| Variant type | Deletion |
| Location | chr17:12993733-12993733 (GRCh38) |
| ClinVar | [VCV4763839](https://www.ncbi.nlm.nih.gov/clinvar/variation/4763839/) |

**All HGVS expressions:** `NC_000017.10:g.12897050del`, `NC_000017.11:g.12993733del`, `NG_015808.1:g.29332del`, `NM_001165962.2:c.2087del`, `NM_018127.7:c.2207del`, `NM_173717.2:c.2204del`

## Computational & population evidence {#evidence}

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

- **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 3.642, GERP -0.028, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.02, pLI 2.8305e-27. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **within the last 50 nt of the penultimate exon (23 of 24, 46 nt from its 3' end)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion 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 **8.47e-05%** (nfe) · 1/1,180,028 in the highest group · 1/1,461,892 alleles overall — very rare (popmax 8.47e-05%, 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.*

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

**ELAC2** population constraint: LOEUF 1.02, pLI 2.8305e-27, missense-Z -0.074804. *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 **736** lies in a modified residue (phosphoserine).

AlphaFold model confidence (whole protein): pLDDT 82.81, 63% of residues very-high.

**10 experimental structure(s)** (PDB): [8CBL](https://www.rcsb.org/structure/8CBL), [8RR1](https://www.rcsb.org/structure/8RR1), [8RR3](https://www.rcsb.org/structure/8RR3), [8RR4](https://www.rcsb.org/structure/8RR4), [8Z0P](https://www.rcsb.org/structure/8Z0P), [8Z1F](https://www.rcsb.org/structure/8Z1F) — incl. mutant structure 8RR1.

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

*Describes the biological roles of ELAC2 (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:** ELAC2's established molecular role includes RNA binding.


### Pathways affected {#pathways}

ELAC2 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [rRNA processing in the mitochondrion](https://reactome.org/content/detail/R-HSA-8868766) | curated |
| [tRNA processing in the mitochondrion](https://reactome.org/content/detail/R-HSA-6785470) | curated |
| [tRNA processing in the nucleus](https://reactome.org/content/detail/R-HSA-6784531) | curated |
| [tRNA-derived small RNA (tsRNA or tRNA-related fragment, tRF) biogenesis](https://reactome.org/content/detail/R-HSA-9708296) | curated |

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

**Molecular function:** RNA binding, tRNA-specific ribonuclease activity.

**Biological process:** tRNA 3'-end processing, mitochondrial tRNA 3'-end processing.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-08.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-06-08 |

## Associated conditions {#conditions}

[combined oxidative phosphorylation defect type 17](https://sugi.bio/atlas/disease/combined-oxidative-phosphorylation-defect-type-17/).

**Reported phenotype names (ClinVar):** Combined oxidative phosphorylation defect type 17, Combined oxidative phosphorylation deficiency 17.

## Similar variants {#similar}

Related ELAC2 variant pages (same residue, condition, or type): [ELAC2 p.Cys670fs](/variant/elac2-p-cys670fs), [ELAC2 p.Ile153fs](/variant/elac2-p-ile153fs), [ELAC2 p.Met715fs](/variant/elac2-p-met715fs), [ELAC2 c.432+1del](/variant/elac2-c-432-plus-1del), [ELAC2 c.797+14del](/variant/elac2-c-797-plus-14del), [ELAC2 c.2109-6_2111del](/variant/elac2-c-2109-minus-6-2111del), [ELAC2 p.Ala11fs](/variant/elac2-p-ala11fs), [ELAC2 p.Cys405fs](/variant/elac2-p-cys405fs).

### 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 4763839). 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.*