SUN1

Chr 7

Sad1 and UNC84 domain containing 1

Also known as: UNC84A

NCBI Gene: 23353 ENSG00000164828 UniProt: O94901 OMIM: 607723

The SUN1 protein is a nuclear envelope component that connects the nuclear lamina to the cytoskeleton and is essential for nuclear migration during brain development, particularly for radial neuronal migration in the cerebral cortex. Mutations in SUN1 cause autosomal recessive arthrogryposis multiplex congenita with seizures and intellectual disability, reflecting its critical role in neuronal positioning during development. The gene is highly constrained against loss-of-function variants, indicating that complete loss of SUN1 function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

This gene is a member of the unc-84 homolog family and encodes a nuclear envelope protein with an Unc84 (SUN) domain. The protein is involved in nuclear anchorage and migration. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2019]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.56

Clinical Summary— SUN1

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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

Moderate LoF intolerance

LoF Constraint?

0.56LOEUF

pLI 0.000

Z-score 3.92

OE 0.37 (0.26–0.56)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.33Z-score

OE missense 0.96 (0.89–1.03)

474 obs / 494.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.26–0.56)

0≤0.351.4

Missense OE?0.96 (0.89–1.03)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 17 / 45.5Missense obs/exp: 474 / 494.7Syn Z: -1.19

This gene — mechanism propensity

0.6452th %ile

GOF

0.4184th %ile

LOF

0.3841th %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.