SEPHS2

Chr 16

selenophosphate synthetase 2

Also known as: SPS2

NCBI Gene: 22928 ENSG00000179918 UniProt: Q99611 OMIM: 606218

The protein is a selenophosphate synthase that generates the selenium donor required for selenocysteine biosynthesis, catalyzing the formation of selenophosphate from selenide and ATP. Mutations cause autosomal recessive pontocerebellar hypoplasia type 2D, a severe neurodevelopmental disorder affecting the brainstem and cerebellum. The gene shows minimal constraint to loss-of-function variants (pLI 0.002, LOEUF 0.998), which is consistent with the recessive inheritance pattern where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes an enzyme that catalyzes the production of monoselenophosphate (MSP) from selenide and ATP. MSP is the selenium donor required for synthesis of selenocysteine (Sec), which is co-translationally incorporated into selenoproteins at in-frame UGA codons that normally signal translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, the Sec insertion sequence (SECIS) element, which is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. This protein is itself a selenoprotein containing a Sec residue at its active site, suggesting the existence of an autoregulatory mechanism. It is preferentially expressed in tissues implicated in the synthesis of selenoproteins and in sites of blood cell development. A pseudogene for this locus has been identified on chromosome 5. [provided by RefSeq, May 2017]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.00

Clinical Summary— SEPHS2

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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

55 VUS of 56 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.00LOEUF

pLI 0.002

Z-score 1.58

OE 0.51 (0.28–1.00)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.76Z-score

OE missense 0.69 (0.61–0.79)

184 obs / 264.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.51 (0.28–1.00)

0≤0.351.4

Missense OE?0.69 (0.61–0.79)

0≤0.61.4

Synonymous OE?0.82

0≤1.21.6

LoF obs/exp: 6 / 11.9Missense obs/exp: 184 / 264.8Syn Z: 1.51

This gene — mechanism propensity

0.6551th %ile

GOF

0.6052th %ile

LOF

0.3649th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

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.

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

ClinVar Variant Classifications

56 submitted variants in ClinVar

ClinVar

Classification Summary

VUS55

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	55	55
Likely Benign	1	1
Benign	0	0
Total	56	56

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap SEPHS2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →