FARS2

Chr 6AR

phenylalanyl-tRNA synthetase 2, mitochondrial

Also known as: COXPD14, FARS1, HSPC320, PheRS, SPG77, mtPheRS

NCBI Gene: 10667ENSG00000145982UniProt: O95363

This gene encodes a protein that transfers phenylalanine to its cognate tRNA. This protein localizes to the mitochondrion and plays a role in mitochondrial protein translation. Mutations in this gene can cause combined oxidative phosphorylation deficiency 14 (Alpers encephalopathy). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

Primary Disease Associations & Inheritance

Combined oxidative phosphorylation deficiency 14MIM #614946
AR
Spastic paraplegia 77, autosomal recessiveMIM #617046
AR
706
ClinVar variants
54
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— FARS2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
54 Pathogenic / Likely Pathogenic· 176 VUS of 706 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.15LOEUF
pLI 0.000
Z-score 1.04
OE 0.75 (0.50–1.15)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.68Z-score
OE missense 0.88 (0.79–0.98)
232 obs / 263.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.75 (0.50–1.15)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.88 (0.79–0.98)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.06
0≤1.21.6
LoF obs/exp: 15 / 20.0Missense obs/exp: 232 / 263.1Syn Z: -0.50

ClinVar Variant Classifications

706 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37
Likely Pathogenic17
VUS176
Likely Benign134
Benign29
Conflicting3
37
Pathogenic
17
Likely Pathogenic
176
VUS
134
Likely Benign
29
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
1
31
0
37
Likely Pathogenic
5
7
5
0
17
VUS
1
144
30
1
176
Likely Benign
0
1
50
83
134
Benign
0
2
26
1
29
Conflicting
—3
Total1115514285396

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

FARS2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

FARS2-related neurometabolic disorder

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Combined oxidative phosphorylation deficiency 14

MIM #614946

Molecular basis of disorder known

Autosomal recessive

Spastic paraplegia 77, autosomal recessive

MIM #617046

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System.
Li B et al.·Circulation
2024
Clinical and molecular characterization of novel FARS2 variants causing neonatal mitochondrial disease.
Chen W et al.·Mol Genet Metab
2023Case report
FARS2 mutation and epilepsy: Possible link with early-onset epileptic encephalopathy.
Cho JS et al.·Epilepsy Res
2017Review
Clinical findings in a patient with FARS2 mutations and early-infantile-encephalopathy with epilepsy.
Raviglione F et al.·Am J Med Genet A
2016Case report
A pseudo-homozygous missense variant and Alu-mediated exon 5 deletion in FARS2 causing spastic paraplegia 77.
Lin SH et al.·Ann Clin Transl Neurol
2024Case report
New insights into the phenotype of FARS2 deficiency.
Vantroys E et al.·Mol Genet Metab
2017Case report
Mutations in FARS2 and non-fatal mitochondrial dysfunction in two siblings.
Vernon HJ et al.·Am J Med Genet A
2015
Kinetic and structural changes in HsmtPheRS, induced by pathogenic mutations in human FARS2.
Kartvelishvili E et al.·Protein Sci
2017Case report
FARS2 deficiency; new cases, review of clinical, biochemical, and molecular spectra, and variants interpretation based on structural, functional, and evolutionary significance.
Almannai M et al.·Mol Genet Metab
2018Review
A Newly Identified Missense Mutation in FARS2 Causes Autosomal-Recessive Spastic Paraplegia.
Yang Y et al.·Hum Mutat
2016
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools