# NM_018127.7(ELAC2):c.897T>C (p.Pro299=)

https://sugi.bio/variant/elac2-p-pro299

## Summary

**ELAC2 p.Pro299= (c.897T>C)** is classified **Likely benign** in ELAC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-19). Very rare (popmax 8.47e-05%, nfe); Associated with combined oxidative phosphorylation defect type 17.

**At a glance:** Likely benign · review: Single submitter · rsID rs2041029702 · 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 classified as likely benign — not considered disease-causing, 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.Pro299= |
| Coding change (HGVS c.) | c.897T>C |
| MANE Select transcript | [NM_018127](https://www.ncbi.nlm.nih.gov/nuccore/NM_018127) |
| dbSNP | [rs2041029702](https://www.ncbi.nlm.nih.gov/snp/rs2041029702/) |
| Variant type | single nucleotide variant |
| Location | chr17:13005075-13005075 (GRCh38) |
| ClinVar | [VCV2776477](https://www.ncbi.nlm.nih.gov/clinvar/variation/2776477/) |

**All HGVS expressions:** `NC_000017.10:g.12908392A>G`, `NC_000017.11:g.13005075A>G`, `NG_015808.1:g.17990T>C`, `NM_001165962.2:c.777T>C`, `NM_018127.7:c.897T>C`, `NM_173717.2:c.897T>C`

## 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 -0.014, GERP -4.22, phastCons 0.067 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.737**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>C, Δ0.57 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Pangolin: Δ**0.21** (gain), gain 0.21 / loss 0.11. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,024 in the highest group · 1/1,614,198 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 **299** lies in an α-helix.

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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-19.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-19 |

## 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.Pro299Thr](/variant/elac2-p-pro299thr), [ELAC2 c.1080-1G>C](/variant/elac2-c-1080-minus-1g-c), [ELAC2 c.1423+1G>A](/variant/elac2-c-1423-plus-1g-a), [ELAC2 c.1908+1G>A](/variant/elac2-c-1908-plus-1g-a), [ELAC2 c.245+2T>A](/variant/elac2-c-245-plus-2t-a), [ELAC2 p.Arg497Ter](/variant/elac2-p-arg497ter), [ELAC2 p.Gln18Ter](/variant/elac2-p-gln18ter), [ELAC2 p.Glu30Ter](/variant/elac2-p-glu30ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 2776477). 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.*