FA2H

Chr 16AR

fatty acid 2-hydroxylase

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

NCBI Gene: 79152ENSG00000103089UniProt: Q7L5A8

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]

Primary Disease Associations & Inheritance

Spastic paraplegia 35, autosomal recessiveMIM #612319
AR
479
ClinVar variants
93
Pathogenic / LP
0.15
pLI score
0
Active trials
Clinical Summary— FA2H
🧬
Gene-Disease Validity (ClinGen)
hereditary spastic paraplegia 35 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.
📋
ClinVar Variants
93 Pathogenic / Likely Pathogenic· 189 VUS of 479 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.46Z-score
OE missense 0.91 (0.80–1.03)
179 obs / 197.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.26 (0.14–0.56)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.80–1.03)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.07
0≤1.21.6
LoF obs/exp: 5 / 18.9Missense obs/exp: 179 / 197.0Syn Z: -0.52

ClinVar Variant Classifications

479 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic57
Likely Pathogenic36
VUS189
Likely Benign128
Benign34
Conflicting35
57
Pathogenic
36
Likely Pathogenic
189
VUS
128
Likely Benign
34
Benign
35
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
7
38
1
57
Likely Pathogenic
15
14
7
0
36
VUS
1
126
57
5
189
Likely Benign
0
8
53
67
128
Benign
0
0
29
5
34
Conflicting
—35
Total2715518478479

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

View in ClinVar →

Protein Context — Lollipop Plot

FA2H · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

FA2H-related spastic paraplegia

definitive
ARLoss Of FunctionAbsent Gene Product
Eye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Spastic paraplegia 35, autosomal recessive

MIM #612319

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — FA2H
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Neurodegeneration with brain iron accumulation.
Hayflick SJ et al.·Handb Clin Neurol
2018Review
Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis.
He H et al.·J Allergy Clin Immunol
2021
Neurodegeneration with Brain Iron Accumulation.
Schipper DA et al.·Adv Exp Med Biol
2025Review
Hereditary ataxias and paraparesias: clinical and genetic update.
Parodi L et al.·Curr Opin Neurol
2018Review
Clinical, Radiological, and Genetic Profile of Patients with FA2H-Associated Neurodegeneration: Eight Cases from India and a Review of the Literature.
Holla VV et al.·Tremor Other Hyperkinet Mov (N Y)
2026Review
Fatty acid 2-hydroxylase facilitates rotavirus uncoating and endosomal escape.
Li E et al.·Proc Natl Acad Sci U S A
2025
On the complexity of clinical and molecular bases of neurodegeneration with brain iron accumulation.
Tello C et al.·Clin Genet
2018Review
[FA2H gene-associated spastic paraplegia (SPG35) - familial case with late onset].
Rudenskaya GE et al.·Zh Nevrol Psikhiatr Im S S Korsakova
2025Review
KRTA6A and FA2H Are Hub Genes Associated With Cgas-STING-related Immunogenic Cell Death in Lung Adenocarcinoma.
He XU et al.·Cancer Genomics Proteomics
2023
Novel Homozygous FA2H Variant Causing the Full Spectrum of Fatty Acid Hydroxylase-Associated Neurodegeneration (SPG35).
German A et al.·Genes (Basel)
2023Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools