FARS2

Chr 6

phenylalanyl-tRNA synthetase 2, mitochondrial

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

NCBI Gene: 10667 ENSG00000145982 UniProt: O95363

The protein charges mitochondrial tRNA with phenylalanine, which is essential for mitochondrial protein synthesis. Autosomal recessive mutations cause combined oxidative phosphorylation deficiency 14 (Alpers encephalopathy) and spastic paraplegia 77 through impaired mitochondrial translation. The pathogenic mechanism involves defective aminoacylation of mitochondrial tRNA(Phe), leading to respiratory chain dysfunction.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtCombined oxidative phosphorylation deficiency 14

UniProtSpastic paraplegia 77, autosomal recessive

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.15

LOEUF

LOF

Mechanism· G2P

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GeneReview available — FARS2

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

0.68Z-score

OE missense 0.88 (0.79–0.98)

232 obs / 263.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.75 (0.50–1.15)

0≤0.351.4

Missense OE?0.88 (0.79–0.98)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 15 / 20.0Missense obs/exp: 232 / 263.1Syn Z: -0.50

Background carrier burden — how many people carry a rare variant somewhere in FARS2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 83

573 rare PASS variants

Rare truncating (LoF)

1 in 1,300

80 rare PASS variants

Rare synonymous (reference)

1 in 150

254 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FARS2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 120	1 in 1,100
South Asian	~43k	1 in 110	1 in 2,200
Remaining (unassigned)	~30k	1 in 79	1 in 1,800
European (Finnish)	~27k	1 in 390	≈ 1 in 13,000
Admixed American	~22k	1 in 97	1 in 2,400
African / African American	~21k	1 in 84	1 in 2,500
East Asian	~20k	1 in 80	1 in 3,300
Ashkenazi Jewish	~13k	1 in 170	1 in 1,500
Middle Eastern	~2,884	1 in 63	1 in 570

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 6 coding exons well covered in gnomAD exomes and genomes.? see exons ↓