AMELY

Chr Y

amelogenin Y-linked

Also known as: AMGL, AMGY

NCBI Gene: 266 ENSG00000099721 UniProt: Q99218 OMIM: 410000

AMELY encodes an extracellular matrix protein that regulates crystallite formation and mineralization during tooth enamel development. Mutations cause amelogenesis imperfecta affecting tooth enamel structure and quality. The gene shows low constraint against loss-of-function variants and inheritance pattern varies depending on the specific variant and family history.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the amelogenin family of extracellular matrix proteins. Amelogenins are involved in biomineralization during tooth enamel development. Mutations in a related gene on chromosome X cause X-linked amelogenesis imperfecta. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.95

Clinical Summary— AMELY

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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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ClinVar Variants

1 VUS of 3 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.95LOEUF

pLI 0.000

Z-score -1.12

OE 1.70 (0.76–1.95)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.13Z-score

OE missense 1.06 (0.81–1.42)

33 obs / 31.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.70 (0.76–1.95)

0≤0.351.4

Missense OE?1.06 (0.81–1.42)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 5 / 2.9Missense obs/exp: 33 / 31.0Syn Z: -0.36

This gene — mechanism propensity

0.83top 10%

GOF

0.77top 25%

LOF

0.10100th %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.

ClinVar Variant Classifications

3 submitted variants in ClinVar

ClinVar

Classification Summary

VUS1

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	1	1
Likely Benign	0	0
Benign	0	0
Total	1	1

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

56 pathogenic / likely-pathogenic (of 78) ClinVar copy-number / structural variants overlap AMELY — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →