FAM174B

Chr 15

family with sequence similarity 174 member B

NCBI Gene: 400451 ENSG00000185442 UniProt: Q3ZCQ3

The protein is essential for Golgi structural integrity and involved in Golgi organization. Mutations cause autosomal recessive developmental and epileptic encephalopathy with microcephaly, characterized by early-onset seizures, severe developmental delay, and progressive microcephaly. This gene shows low constraint to loss-of-function variation in the general population.

ResearchSummary from RefSeq, UniProt

Involved in Golgi organization. Located in Golgi apparatus and plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.83

Clinical Summary— FAM174B

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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?

1.83LOEUF

pLI 0.002

Z-score 0.01

OE 0.99 (0.47–1.83)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.85Z-score

OE missense 1.29 (1.08–1.54)

89 obs / 69.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.99 (0.47–1.83)

0≤0.351.4

Missense OE?1.29 (1.08–1.54)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 4 / 4.0Missense obs/exp: 89 / 69.1Syn Z: -0.66

This gene — mechanism propensity

0.6648th %ile

GOF

0.6345th %ile

LOF

0.4135th %ile

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

DNprediction above median

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.