STPG4

Chr 2

sperm-tail PG-rich repeat containing 4

Also known as: C2orf61, GSE

NCBI Gene: 285051 ENSG00000239605 UniProt: Q8N801

The protein is a maternal factor that regulates epigenetic chromatin reprogramming during early zygotic development by inducing conversion of 5-methylcytosine to 5-hydroxymethylcytosine in gametic DNA demethylation. Currently, no human diseases have been definitively associated with STPG4 mutations in the medical literature. The gene shows low constraint against loss-of-function variants (pLI = 0.0001), suggesting that complete loss of function may be tolerated.

Summary from RefSeq, UniProt

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Active trials

Pubs (1 yr)

P/LP submissions

—

P/LP missense

1.14

LOEUF

Multiple*

Mechanism· predicted

Clinical Summary— STPG4

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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

14 unique Pathogenic / Likely Pathogenic· 7 VUS of 24 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

1.14LOEUF

pLI 0.000

Z-score 1.21

OE 0.63 (0.37–1.14)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint

-0.86Z-score

OE missense 1.21 (1.06–1.38)

162 obs / 134.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios

LoF OE0.63 (0.37–1.14)

0≤0.351.4

Missense OE1.21 (1.06–1.38)

0≤0.61.4

Synonymous OE1.25

0≤1.21.6

LoF obs/exp: 8 / 12.6Missense obs/exp: 162 / 134.0Syn Z: -1.39

0.6745th %ile

GOF

0.73top 25%

LOF

0.3940th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

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.