# NM_001083614.2(EARS2):c.1556del (p.Lys519fs)

https://sugi.bio/variant/ears2-p-lys519fs

## Summary

**EARS2 p.Lys519fs (c.1556del)** is classified **Uncertain significance** in EARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-22). No gnomAD frequency available for this variant.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2506830195 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the EARS2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EARS2](https://sugi.bio/atlas/gene/EARS2/) |
| Protein change (HGVS p.) | p.Lys519fs |
| Coding change (HGVS c.) | c.1556del |
| MANE Select transcript | [NM_001083614](https://www.ncbi.nlm.nih.gov/nuccore/NM_001083614) |
| dbSNP | [rs2506830195](https://www.ncbi.nlm.nih.gov/snp/rs2506830195/) |
| Variant type | Deletion |
| Location | chr16:23524387-23524387 (GRCh38) |
| ClinVar | [VCV2502597](https://www.ncbi.nlm.nih.gov/clinvar/variation/2502597/) |

**All HGVS expressions:** `NC_000016.10:g.23524388del`, `NC_000016.9:g.23535709del`, `NG_027752.2:g.37989del`, `NM_001083614.2:c.1556del`, `NM_133451.1:c.1555delA`, `NR_003501.2:n.1563del`

## 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 0.824, GERP 0.74, phastCons 0.392 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.138, pLI 7.0535e-14. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (9 of 9)** — 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: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**EARS2** population constraint: LOEUF 1.138, pLI 7.0535e-14, missense-Z 0.080959; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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):

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

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 89.84, 79% of residues very-high.

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

*Describes the biological roles of EARS2 (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:** EARS2's established molecular role includes glutamate-tRNA ligase activity.


### Pathways affected {#pathways}

EARS2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial tRNA aminoacylation](https://reactome.org/content/detail/R-HSA-379726) | electronic |

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

**Molecular function:** glutamate-tRNA ligase activity, glutamate-tRNA(Gln) ligase activity.

**Biological process:** glutamyl-tRNA aminoacylation, tRNA aminoacylation for mitochondrial protein translation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-11-22.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-11-22 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related EARS2 variant pages (same residue, condition, or type): [EARS2 p.Cys140fs](/variant/ears2-p-cys140fs), [EARS2 p.Lys471fs](/variant/ears2-p-lys471fs), [EARS2 p.Phe71fs](/variant/ears2-p-phe71fs), [EARS2 c.486-4_487del](/variant/ears2-c-486-minus-4-487del), [EARS2 c.(?_-8](/variant/ears2-c-minus-8), [EARS2 p.Gly240fs](/variant/ears2-p-gly240fs), [EARS2 p.Leu424fs](/variant/ears2-p-leu424fs), [EARS2 p.Lys66fs](/variant/ears2-p-lys66fs).

### 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 2502597). 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.*