FA2H

Chr 16AR

fatty acid 2-hydroxylase

Also known as: FAAH, FAH1, FAXDC1, SCS7, SPG35

NCBI Gene: 79152 ENSG00000103089 UniProt: Q7L5A8 OMIM: 611026

This protein catalyzes the synthesis of 2-hydroxysphingolipids in the endoplasmic reticulum, which are essential components of myelin. Mutations cause autosomal recessive spastic paraplegia 35, a leukodystrophy characterized by dysmyelination with spastic paraparesis and variable dystonia. The pathogenic mechanism involves loss of function leading to defective myelin formation and maintenance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein that catalyzes the synthesis of 2-hydroxysphingolipids, a subset of sphingolipids that contain 2-hydroxy fatty acids. Sphingolipids play roles in many cellular processes and their structural diversity arises from modification of the hydrophobic ceramide moiety, such as by 2-hydroxylation of the N-acyl chain, and the existence of many different head groups. Mutations in this gene have been associated with leukodystrophy dysmyelinating with spastic paraparesis with or without dystonia.[provided by RefSeq, Mar 2010]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.561 OMIM phenotype

Clinical Summary— FA2H

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Gene-Disease Validity (ClinGen)

hereditary spastic paraplegia 35 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

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ClinVar Variants

70 unique Pathogenic / Likely Pathogenic· 167 VUS of 434 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.56LOEUF

pLI 0.147

Z-score 2.96

OE 0.26 (0.14–0.56)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.46Z-score

OE missense 0.91 (0.80–1.03)

179 obs / 197.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.26 (0.14–0.56)

0≤0.351.4

Missense OE?0.91 (0.80–1.03)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 5 / 18.9Missense obs/exp: 179 / 197.0Syn Z: -0.52

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveFA2H-related spastic paraplegiaLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6841th %ile

GOF

0.5464th %ile

LOF

0.3162th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

434 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33

Likely Pathogenic37

VUS167

Likely Benign127

Benign34

Conflicting34

Pathogenic

Likely Pathogenic

167

VUS

127

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	20	8	4	1	33
Likely Pathogenic	19	18	0	0	37
VUS	1	132	29	5	167
Likely Benign	0	8	52	67	127
Benign	0	0	29	5	34
Conflicting	—				34
Total	40	166	114	78	432

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

View in ClinVar →

27 pathogenic / likely-pathogenic (of 56) ClinVar copy-number / structural variants overlap FA2H — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →