SARS1

Chr 1AR

seryl-tRNA synthetase 1

Also known as: NEDMAS, SARS, SERRS, SERS

NCBI Gene: 6301 ENSG00000031698 UniProt: P49591 OMIM: 607529

The encoded enzyme catalyzes the transfer of L-serine to tRNA(Ser), a critical step in protein synthesis. Biallelic mutations cause neurodevelopmental disorder with microcephaly, ataxia, and seizures, inherited in an autosomal recessive pattern. The gene is highly constrained against loss-of-function variation in the general population.

OMIM ResearchSummary from RefSeq, OMIM

This gene belongs to the class II amino-acyl tRNA family. The encoded enzyme catalyzes the transfer of L-serine to tRNA (Ser) and is related to bacterial and yeast counterparts. Multiple alternatively spliced transcript variants have been described but the biological validity of all variants is unknown. [provided by RefSeq, Jul 2010]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.211 OMIM phenotype

Clinical Summary— SARS1

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Gene-Disease Validity (ClinGen)

neurodevelopmental disorder with microcephaly, ataxia, and seizures · ARLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 54 VUS of 86 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.21LOEUF

pLI 0.999

Z-score 4.70

OE 0.07 (0.03–0.21)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.66Z-score

OE missense 0.57 (0.50–0.65)

170 obs / 299.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.07 (0.03–0.21)

0≤0.351.4

Missense OE?0.57 (0.50–0.65)

0≤0.61.4

Synonymous OE?0.82

0≤1.21.6

LoF obs/exp: 2 / 29.6Missense obs/exp: 170 / 299.4Syn Z: 1.48

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedSARS1-related neurodevelopmental disorderDNAD

moderateSARS1-related neurodevelopmental disorder with microcephaly, ataxia, and seizuresOTHERAR

This gene — mechanism propensity

0.4983th %ile

GOF

0.4480th %ile

LOF

0.4726th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.21

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNComplementation assays in S. cerevisiae and serylation assays in both yeast strains and patient fibroblasts proved a loss-of-function, dominant negative effect.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 36041817 ↗

ClinVar Variant Classifications

86 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic2

VUS54

Likely Benign9

Benign5

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	1	1	0	0	2
VUS	1	50	2	1	54
Likely Benign	0	2	1	6	9
Benign	0	0	3	2	5
Total	2	54	6	9	71

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 33) ClinVar copy-number / structural variants overlap SARS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →