ASAH1

Chr 8AR

N-acylsphingosine amidohydrolase 1

Also known as: AC, ACDase, ASAH, PHP, PHP32, SMAPME

NCBI Gene: 427 ENSG00000104763 UniProt: Q13510 OMIM: 613468

The protein functions as a lysosomal ceramidase that hydrolyzes ceramides into sphingosine and fatty acids, regulating bioactive sphingolipid levels that control cellular processes including proliferation, apoptosis, and differentiation. Mutations cause two autosomal recessive disorders: Farber lipogranulomatosis (a lysosomal storage disorder) and spinal muscular atrophy with progressive myoclonic epilepsy (affecting neuromuscular and neurological systems). The gene is highly constrained against loss-of-function variants (LOEUF 1.18), reflecting its essential cellular role.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the acid ceramidase family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. Processing of this preproprotein generates alpha and beta subunits that heterodimerize to form the mature lysosomal enzyme, which catalyzes the degradation of ceramide into sphingosine and free fatty acid. This enzyme is overexpressed in multiple human cancers and may play a role in cancer progression. Mutations in this gene are associated with the lysosomal storage disorder, Farber lipogranulomatosis, and a neuromuscular disorder, spinal muscular atrophy with progressive myoclonic epilepsy. [provided by RefSeq, Oct 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.182 OMIM phenotypes

Clinical Summary— ASAH1

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Gene-Disease Validity (ClinGen)

ASAH1-related sphingolipidosis · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

132 unique Pathogenic / Likely Pathogenic· 357 VUS of 1045 total submissions

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GeneReview available — ASAH1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.18LOEUF

pLI 0.000

Z-score 0.85

OE 0.82 (0.58–1.18)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-2.21Z-score

OE missense 1.42 (1.29–1.56)

310 obs / 218.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.82 (0.58–1.18)

0≤0.351.4

Missense OE?1.42 (1.29–1.56)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 21 / 25.6Missense obs/exp: 310 / 218.2Syn Z: -0.05

ClinVar Variant Classifications

1045 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic68

Likely Pathogenic64

VUS357

Likely Benign401

Benign109

Conflicting27

Pathogenic

Likely Pathogenic

357

VUS

401

Likely Benign

109

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	41	17	10	0	68
Likely Pathogenic	34	28	2	0	64
VUS	5	290	56	6	357
Likely Benign	0	7	252	142	401
Benign	0	8	101	0	109
Conflicting	—				27
Total	80	350	421	148	1,026

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

View in ClinVar →

79 pathogenic / likely-pathogenic (of 100) ClinVar copy-number / structural variants overlap ASAH1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →