SEPSECS

Chr 4AR

Sep (O-phosphoserine) tRNA:Sec (selenocysteine) tRNA synthase

Also known as: LP, PCH2D, SLA, SLA-p35, SLA/LP, SecS

NCBI Gene: 51091 ENSG00000109618 UniProt: Q9HD40 OMIM: 613009

This enzyme converts O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec), which is essential for selenoprotein biosynthesis. Biallelic mutations cause pontocerebellar hypoplasia type 2D, an autosomal recessive neurodevelopmental disorder affecting the brainstem and cerebellum. The gene shows very low constraint against loss-of-function variants (pLI near zero), consistent with recessive inheritance where heterozygous carriers are typically unaffected.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The amino acid selenocysteine is the only amino acid that does not have its own tRNA synthetase. Instead, this amino acid is synthesized on its cognate tRNA in a three step process. The protein encoded by this gene catalyzes the third step in the process, the conversion of O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec).[provided by RefSeq, Mar 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.991 OMIM phenotype

Clinical Summary— SEPSECS

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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

111 unique Pathogenic / Likely Pathogenic· 186 VUS of 686 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SEPSECS

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?

0.99LOEUF

pLI 0.000

Z-score 1.60

OE 0.65 (0.44–0.99)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.02Z-score

OE missense 1.00 (0.90–1.10)

269 obs / 270.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.65 (0.44–0.99)

0≤0.351.4

Missense OE?1.00 (0.90–1.10)

0≤0.61.4

Synonymous OE?0.73

0≤1.21.6

LoF obs/exp: 16 / 24.6Missense obs/exp: 269 / 270.0Syn Z: 2.10

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSEPSECS-related pontocerebellar hypoplasiaLOFAR

This gene — mechanism propensity

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

0.74top 25%

GOF

0.3491th %ile

LOF

0.3356th %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

686 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic43

Likely Pathogenic68

VUS186

Likely Benign329

Benign35

Conflicting17

Pathogenic

Likely Pathogenic

186

VUS

329

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	35	2	6	0	43
Likely Pathogenic	60	5	3	0	68
VUS	2	129	49	6	186
Likely Benign	1	3	147	178	329
Benign	0	2	33	0	35
Conflicting	—				17
Total	98	141	238	184	678

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

View in ClinVar →

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