FAM83H

Chr 8AD

scaffolding CK1 anchoring protein H

Also known as: AI3, AI3A, FAM83H

NCBI Gene: 286077 ENSG00000180921 UniProt: Q6ZRV2 OMIM: 130900

The protein encoded by this gene plays a major role in the structural organization and calcification of developing tooth enamel and may regulate epithelial cell migration through keratin cytoskeleton disassembly. Mutations cause amelogenesis imperfecta type IIIA, a dental disorder affecting enamel formation, with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.89, LOEUF 0.36), indicating intolerance to protein disruption.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene plays an important role in the structural development and calcification of tooth enamel. Defects in this gene are a cause of amelogenesis imperfecta type 3 (AI3). [provided by RefSeq, Mar 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.362 OMIM phenotypes

Clinical Summary— FAM83H

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.89) — some intolerance to loss-of-function variants.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.36LOEUF

pLI 0.892

Z-score 4.16

OE 0.17 (0.09–0.36)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-0.42Z-score

OE missense 1.04 (0.98–1.10)

824 obs / 791.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.17 (0.09–0.36)

0≤0.351.4

Missense OE?1.04 (0.98–1.10)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 5 / 29.3Missense obs/exp: 824 / 791.0Syn Z: -2.10

This gene — mechanism propensity

0.4587th %ile

GOF

0.5661th %ile

LOF

0.67top 25%

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

LOFprediction above median · LOEUF 0.36

GOF1 literature citation

DN1 literature citation

Literature Evidence

DNHart et al. (2009) noted that all of the FAM83H mutations identified in AI3A thus far were nonsense mutations that clustered within a 380-amino acid region, supporting a dominant-negative effect.1

GOFADHCAI is likely caused by gain-of-function effects mediated by truncated FAM83H, which potentially mislocalizes CK1 as part of its pathological mechanism.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References