PHYH

Chr 10AR

phytanoyl-CoA 2-hydroxylase

Also known as: LN1, LNAP1, PAHX, PHYH1, RD

NCBI Gene: 5264ENSG00000107537UniProt: O14832

This gene is a member of the PhyH family and encodes a peroxisomal protein that is involved in the alpha-oxidation of 3-methyl branched fatty acids. Specifically, this protein converts phytanoyl-CoA to 2-hydroxyphytanoyl-CoA. Mutations in this gene have been associated with Refsum disease (RD) and deficient protein activity has been associated with Zellweger syndrome and rhizomelic chondrodysplasia punctata. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Refsum diseaseMIM #266500
AR
558
ClinVar variants
101
Pathogenic / LP
0.00
pLI score
4
Active trials
Clinical Summary— PHYH
🧬
Gene-Disease Validity (ClinGen)
phytanoyl-CoA hydroxylase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
101 Pathogenic / Likely Pathogenic· 195 VUS of 558 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
1.12LOEUF
pLI 0.000
Z-score 1.20
OE 0.68 (0.43–1.12)
Tolerant

Highly tolerant — LoF variants common in population

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.
0.03Z-score
OE missense 0.99 (0.88–1.12)
194 obs / 195.2 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.0.68 (0.43–1.12)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.99 (0.88–1.12)
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.0.96
0≤1.21.6
LoF obs/exp: 11 / 16.2Missense obs/exp: 194 / 195.2Syn Z: 0.29

ClinVar Variant Classifications

558 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic55
Likely Pathogenic46
VUS195
Likely Benign207
Benign37
Conflicting18
55
Pathogenic
46
Likely Pathogenic
195
VUS
207
Likely Benign
37
Benign
18
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
14
2
39
0
55
Likely Pathogenic
30
6
10
0
46
VUS
1
159
29
6
195
Likely Benign
0
2
93
112
207
Benign
0
1
34
2
37
Conflicting
—18
Total45170205120558

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

View in ClinVar →

Protein Context — Lollipop Plot

PHYH · protein map & ClinVar variants

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

Gene2Phenotype Curations

PHYH-related Refsum disease

definitive
ARLoss Of FunctionAbsent Gene Product
EyeSkin
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Refsum disease

MIM #266500

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — PHYH
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Structural and mechanistic studies on the peroxisomal oxygenase phytanoyl-CoA 2-hydroxylase (PhyH).
Schofield CJ et al.·Biochem Soc Trans
2007Review
PHYH c.678+5G>T Leads to In-Frame Exon Skipping and Is Associated With Attenuated Refsum Disease.
Daich Varela M et al.·Invest Ophthalmol Vis Sci
2024
Prognostic role of PHYH for overall survival (OS) in clear cell renal cell carcinoma (ccRCC).
Zhengqi Q et al.·Eur J Med Res
2021
Neurotoxicities of current leukemia therapy.
Pizzo PA et al.·Am J Pediatr Hematol Oncol
1979Review
Genome-Wide Insights Into the Genes and Pathways Shaping Human Foveal Development: Redefining the Genetic Landscape of Foveal Hypoplasia.
Hunt C et al.·Invest Ophthalmol Vis Sci
2025
Identification of PEX7 as the second gene involved in Refsum disease.
van den Brink DM et al.·Am J Hum Genet
2003
Prognostic value of lipid metabolism-related genes in head and neck squamous cell carcinoma.
Xiong Y et al.·Immun Inflamm Dis
2021
Targeted Therapies for Hereditary Peripheral Neuropathies: Systematic Review and Steps Towards a 'treatabolome'.
Jennings MJ et al.·J Neuromuscul Dis
2021Review
Cochlear Implantation in Siblings With Refsum's Disease.
Stähr K et al.·Ann Otol Rhinol Laryngol
2017Case report
Bilateral Iris and Chorioretinal Colobomas in a Child With Suspected Lamb-Shaffer Syndrome.
Hucko LN et al.·Ophthalmic Surg Lasers Imaging Retina
2025Case 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
Eye Diseases HereditaryRetinal DiseaseAchromatopsia

Inherited Retinal Degenerative Disease Registry

RECRUITING
NCT02435940Foundation Fighting BlindnessStarted 2014-06
Rare DisordersUndiagnosed DisordersDisorders of Unknown Prevalence

Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

RECRUITING
NCT01793168Sanford HealthStarted 2010-07
LeukodystrophyWhite Matter DiseaseLeukoencephalopathies

The Myelin Disorders Biorepository Project

RECRUITING
NCT03047369Children's Hospital of PhiladelphiaStarted 2016-12-08
Peroxisome Biogenesis DisorderZellweger Spectrum DisorderRCDP - Rhizomelic Chondrodysplasia Punctata

Longitudinal Natural History Study of Patients With Peroxisome Biogenesis Disorders (PBD)

RECRUITING
NCT01668186McGill University Health Centre/Research Institute of the McGill University Health CentreStarted 2012-01

External Resources

Links to major genomics databases and tools