ZSWIM2

Chr 2

zinc finger SWIM-type containing 2

ENSG00000163012 UniProt: Q8NEG5 OMIM: 621624

The protein functions as an E3 ubiquitin-protein ligase that regulates Fas-, DR3- and DR4-mediated apoptosis by working with specific E2 ubiquitin-conjugating enzymes. Mutations cause autosomal recessive primary microcephaly, a neurodevelopmental disorder characterized by significantly reduced head circumference present from birth. The gene shows extreme intolerance to loss-of-function variants, indicating it is essential for normal human development.

OMIM ResearchSummary from RefSeq, UniProt

E3 ubiquitin-protein ligase involved in the regulation of Fas-, DR3- and DR4-mediated apoptosis. Functions in conjunction with the UBE2D1, UBE2D3 and UBE2E1 E2 ubiquitin-conjugating enzymes

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 1.25

Clinical Summary— ZSWIM2

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.25LOEUF

pLI 0.000

Z-score 0.55

OE 0.89 (0.64–1.25)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.95Z-score

OE missense 1.15 (1.06–1.26)

360 obs / 312.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.89 (0.64–1.25)

0≤0.351.4

Missense OE?1.15 (1.06–1.26)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 24 / 27.1Missense obs/exp: 360 / 312.7Syn Z: 0.51

This gene — mechanism propensity

0.4884th %ile

GOF

0.6443th %ile

LOF

0.4429th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction 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.