PMP22

Chr 17ADAR

peripheral myelin protein 22

Also known as: CIDP, CMT1A, CMT1E, DSS, GAS-3, GAS3, HMSNIA, HNPP

NCBI Gene: 5376 ENSG00000109099 UniProt: Q9NR77 OMIM: 601097

This gene encodes an integral membrane protein that is a major component of myelin in the peripheral nervous system. Mutations cause several inherited peripheral neuropathies including Charcot-Marie-Tooth disease types 1A and 1E, Dejerine-Sottas disease, hereditary neuropathy with liability to pressure palsies, and Roussy-Levy syndrome, with inheritance patterns that are primarily autosomal dominant but can be autosomal recessive. The pathogenic mechanism involves disruption of peripheral myelin structure and function due to altered PMP22 protein levels or function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an integral membrane protein that is a major component of myelin in the peripheral nervous system. Studies suggest two alternately used promoters drive tissue-specific expression. Various mutations of this gene are causes of Charcot-Marie-Tooth disease Type IA, Dejerine-Sottas syndrome, and hereditary neuropathy with liability to pressure palsies. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.396 OMIM phenotypes

Clinical Summary— PMP22

🧬

Gene-Disease Validity (ClinGen)

Charcot-Marie-Tooth disease type 1A · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.91). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

127 unique Pathogenic / Likely Pathogenic· 175 VUS of 457 total submissions

💊

Clinical Trials

6 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — PMP22

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.39LOEUF

pLI 0.910

Z-score 2.58

OE 0.00 (0.00–0.39)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.42Z-score

OE missense 0.88 (0.73–1.06)

79 obs / 90.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.39)

0≤0.351.4

Missense OE?0.88 (0.73–1.06)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 0 / 7.7Missense obs/exp: 79 / 90.1Syn Z: -0.28

This gene — mechanism propensity

0.4190th %ile

GOF

0.6932th %ile

LOF

0.4825th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 43% of P/LP variants are LoF · LOEUF 0.39 · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOFprediction above median · 1 literature citation

DN1 literature citation

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.

Literature Evidence

DNUnlike CMT associated with the PMP22 duplication and a gene-dosage effect, the Ala67Pro mutation is likely to cause a dominant-negative effect, like the majority of DSS and CMT point mutations.1

GOFThis study supported the notion that missense mutations in PMP22 give rise to a CMT phenotype, possibly through a toxic gain-of-function mechanism.2

LOFHNPP is in the majority of cases correlated with heterozygous deletion of the whole PMP22 gene or other mutations leading to functional haploinsufficiency.3

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

457 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic89

Likely Pathogenic38

VUS175

Likely Benign106

Benign18

Conflicting28

Pathogenic

Likely Pathogenic

175

VUS

106

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	38	16	35	0	89
Likely Pathogenic	17	19	2	0	38
VUS	26	117	30	2	175
Likely Benign	0	3	51	52	106
Benign	0	0	18	0	18
Conflicting	—				28
Total	81	155	136	54	454

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

View in ClinVar →

129 pathogenic / likely-pathogenic (of 136) ClinVar copy-number / structural variants overlap PMP22 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →