# NM_020745.4(AARS2):c.149T>G (p.Phe50Cys)

https://sugi.bio/variant/aars2-p-phe50cys

## Summary

**AARS2 p.Phe50Cys (c.149T>G)** is classified **Pathogenic** in AARS2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2014-06-10). AlphaMissense: likely pathogenic (0.8303); Very rare (popmax 0.00017%, nfe); Associated with leukoencephalopathy, progressive, with ovarian failure.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs587777590 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the AARS2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to leukoencephalopathy, progressive, with ovarian failure.

*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) | Childhood |
| Diagnostic panels | AARS2 is a diagnostic-grade gene on 14 Genomics England panels |

**Commonly reported features of CACH syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Dysmyelinating leukodystrophy — Very frequent (99-80%)
- Brain imaging abnormality — Very frequent (99-80%)
- Optic atrophy — Frequent (79-30%)
- Irritability — Frequent (79-30%)
- Seizure — Frequent (79-30%)
- Spasticity — Frequent (79-30%)
- Cerebellar atrophy — Frequent (79-30%)
- Hyperreflexia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018252/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AARS2](https://sugi.bio/atlas/gene/AARS2/) |
| Protein change (HGVS p.) | p.Phe50Cys |
| Coding change (HGVS c.) | c.149T>G |
| MANE Select transcript | [NM_020745](https://www.ncbi.nlm.nih.gov/nuccore/NM_020745) |
| dbSNP | [rs587777590](https://www.ncbi.nlm.nih.gov/snp/rs587777590/) |
| Variant type | single nucleotide variant |
| Location | chr6:44313175-44313175 (GRCh38) |
| ClinVar | [VCV143045](https://www.ncbi.nlm.nih.gov/clinvar/variation/143045/) |

**All HGVS expressions:** `NC_000006.11:g.44280912A>C`, `NC_000006.12:g.44313175A>C`, `NG_031952.1:g.5152T>G`, `NM_020745.4:c.149T>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8303) — concordant with the pathogenic call
- REVEL 0.986 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.419 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.077, GERP 1.89, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in AARS2 (of 5,663 modeled).
- 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.*
- Regional missense constraint: **o/e 0.90** across the covering region of the MANE Select transcript (44,300,550–44,313,323), spanning 12,773 bp. Chi-square p 0.00019. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,726 in the highest group · 2/1,460,620 alleles overall — very rare (popmax 0.00017%, 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}

**AARS2** population constraint: LOEUF 0.752, pLI 1.8233e-15, missense-Z 1.8985; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (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):

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

## Protein context {#protein}

Residue **50** lies in a UniProt-annotated variant site (in lkenp; deleterious only under stress conditions).

AlphaFold model confidence (whole protein): pLDDT 88.05, 62% of residues very-high.

**3 experimental structure(s)** (PDB): [6NLQ](https://www.rcsb.org/structure/6NLQ), [6NLY](https://www.rcsb.org/structure/6NLY), [6NOW](https://www.rcsb.org/structure/6NOW).

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

*Describes the biological roles of AARS2 (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:** AARS2's established molecular role includes alanine-tRNA ligase activity.


### Pathways affected {#pathways}

AARS2 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:** alanine-tRNA ligase activity, peptide lactyltransferase (ATP-dependent) activity.

**Biological process:** mitochondrial alanyl-tRNA aminoacylation, negative regulation of cGAS/STING signaling pathway.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2014-06-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2014-06-10 |

## Associated conditions {#conditions}

[leukoencephalopathy, progressive, with ovarian failure](https://sugi.bio/atlas/disease/leukoencephalopathy-progressive-with-ovarian-failure/).

**Reported phenotype names (ClinVar):** Leukoencephalopathy, progressive, with ovarian failure.

## Similar variants {#similar}

Related AARS2 variant pages (same residue, condition, or type): [AARS2 p.Arg199Cys](/variant/aars2-p-arg199cys), [AARS2 p.Arg521Ter](/variant/aars2-p-arg521ter), [AARS2 p.Arg592Trp](/variant/aars2-p-arg592trp), [AARS2 p.Arg958Ter](/variant/aars2-p-arg958ter), [AARS2 p.Thr782Ile](/variant/aars2-p-thr782ile), [AARS2 p.Ala386Val](/variant/aars2-p-ala386val), [AARS2 p.Arg101His](/variant/aars2-p-arg101his), [AARS2 p.Gly965Arg](/variant/aars2-p-gly965arg).

### 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 143045). 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.*