AMELX

Chr XXLD

amelogenin X-linked

Also known as: AI1E, AIH1, ALGN, AMG, AMGL, AMGX

NCBI Gene: 265 ENSG00000125363 UniProt: Q99217 OMIM: 300391

This gene encodes amelogenin, an extracellular matrix protein that regulates crystallite formation and mineralization during tooth enamel development. Mutations cause X-linked amelogenesis imperfecta type 1E, a condition affecting enamel formation and tooth structure. The inheritance pattern is X-linked dominant.

OMIM ResearchSummary from RefSeq, OMIM, 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 this gene cause X-linked amelogenesis imperfecta. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismXLDLOEUF 0.951 OMIM phenotype

Clinical Summary— AMELX

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Population Constraint (gnomAD)

Low constraint (pLI 0.07) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

21 unique Pathogenic / Likely Pathogenic· 14 VUS of 65 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?

0.95LOEUF

pLI 0.075

Z-score 1.68

OE 0.37 (0.17–0.95)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.96Z-score

OE missense 0.71 (0.57–0.88)

59 obs / 83.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.17–0.95)

0≤0.351.4

Missense OE?0.71 (0.57–0.88)

0≤0.61.4

Synonymous OE?1.34

0≤1.21.6

LoF obs/exp: 3 / 8.2Missense obs/exp: 59 / 83.6Syn Z: -1.54

This gene — mechanism propensity

0.78top 25%

GOF

0.6540th %ile

LOF

0.11100th %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

65 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15

Likely Pathogenic6

VUS14

Likely Benign6

Benign9

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	7	3	1	15
Likely Pathogenic	4	2	0	0	6
VUS	0	14	0	0	14
Likely Benign	0	1	1	4	6
Benign	0	1	5	3	9
Total	8	25	9	8	50

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

View in ClinVar →

77 pathogenic / likely-pathogenic (of 89) ClinVar copy-number / structural variants overlap AMELX — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →