# NM_001083614.2(EARS2):c.212del (p.Phe71fs)

https://sugi.bio/variant/ears2-p-phe71fs

## Summary

**EARS2 p.Phe71fs (c.212del)** is classified **Pathogenic/Likely pathogenic** in EARS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-08-12). Very rare (popmax 0.00133%, afr); Associated with leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs778413603 · 4 submitters · 1 linked condition · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the EARS2 gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to leukoencephalopathy-thalamus and brainstem anomalies-high lactate 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) | No data available |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | EARS2 is a diagnostic-grade gene on 13 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013381/index) · [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.Phe71fs |
| Coding change (HGVS c.) | c.212del |
| MANE Select transcript | [NM_001083614](https://www.ncbi.nlm.nih.gov/nuccore/NM_001083614) |
| dbSNP | [rs778413603](https://www.ncbi.nlm.nih.gov/snp/rs778413603/) |
| Variant type | Deletion |
| Location | chr16:23552232-23552232 (GRCh38) |
| ClinVar | [VCV419276](https://www.ncbi.nlm.nih.gov/clinvar/variation/419276/) |

**All HGVS expressions:** `NC_000016.10:g.23552233del`, `NC_000016.9:g.23563554del`, `NG_027752.2:g.10144del`, `NM_001083614.1:c.212del`, `NM_001083614.1:c.212delT`, `NM_001083614.2:c.212del`, `NM_001083614.2:c.212delT`, `NM_001308211.1:c.212del`, `NR_003501.2:n.219del`

## 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 4.305, GERP 0.712, phastCons 1 — highly conserved position (PP3-type support)
- 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 exon 2 of 9**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 33.0**. 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 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 **0.00133%** (afr) · FAF95 0.000292% · FAF99 0.000211% · 1/74,930 in the highest group · 10/1,614,094 alleles overall — very rare (popmax 0.00133%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,488 |
| African / African-American (grpmax) | 0.00133% | 74,930 |
| European (non-Finnish) | 0.000678% | 147,505 |

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}

**EARS2** population constraint: LOEUF 1.138, pLI 7.0535e-14, missense-Z 0.080959; 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):

- **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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-08-12.

**Submitter consensus:** conflicting (3 Pathogenic, 1 Likely pathogenic).

**Submission history:** 4 submissions (2022–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-08-12 |
| Genetics and Molecular Pathology, SA Pathology | Pathogenic | criteria provided, single submitter | clinical testing | 2022-12-19 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2023-07-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-23 |

## Associated conditions {#conditions}

[leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome](https://sugi.bio/atlas/disease/leukoencephalopathy-thalamus-and-brainstem-anomalies-high-lactate-syndrome/).

**Reported phenotype names (ClinVar):** Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, not provided, none provided, LEUKOENCEPHALOPATHY WITH THALAMUS AND BRAINSTEM INVOLVEMENT AND HIGH LACTATE, Combined oxidative phosphorylation deficiency 12.

## Similar variants {#similar}

Related EARS2 variant pages (same residue, condition, or type): [EARS2 p.Cys140fs](/variant/ears2-p-cys140fs), [EARS2 c.(?_-8](/variant/ears2-c-minus-8), [EARS2 p.Gly240fs](/variant/ears2-p-gly240fs), [EARS2 c.1488+61del](/variant/ears2-c-1488-plus-61del), [EARS2 p.Pro428fs](/variant/ears2-p-pro428fs), [EARS2 p.Arg107His](/variant/ears2-p-arg107his), [EARS2 p.Arg108Trp](/variant/ears2-p-arg108trp), [EARS2 p.Cys167Tyr](/variant/ears2-p-cys167tyr).

### 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 419276). 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.*