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

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 OE0.17 (0.09–0.36)

0≤0.351.4

Missense OE1.04 (0.98–1.10)

0≤0.61.4

Synonymous OE1.14

0≤1.21.6

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

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.PMID:19220331

GOFADHCAI is likely caused by gain-of-function effects mediated by truncated FAM83H, which potentially mislocalizes CK1 as part of its pathological mechanism.PMID:26788537

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