FARS2

Chr 6AR

phenylalanyl-tRNA synthetase 2, mitochondrial

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

NCBI Gene: 10667 ENSG00000145982 UniProt: O95363 OMIM: 611592

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 OMIM 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 OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.152 OMIM phenotypes

Clinical Summary— FARS2

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

88 unique Pathogenic / Likely Pathogenic· 270 VUS of 629 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — FARS2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveFARS2-related neurometabolic disorderLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6258th %ile

GOF

0.4283th %ile

LOF

0.3843th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

629 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic49

Likely Pathogenic39

VUS270

Likely Benign196

Benign49

Conflicting23

Pathogenic

Likely Pathogenic

270

VUS

196

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	19	6	24	0	49
Likely Pathogenic	13	20	6	0	39
VUS	1	238	27	4	270
Likely Benign	0	6	61	129	196
Benign	0	6	39	4	49
Conflicting	—				23
Total	33	276	157	137	626

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

View in ClinVar →

50 pathogenic / likely-pathogenic (of 83) ClinVar copy-number / structural variants overlap FARS2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →