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

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]

Primary Disease Associations & Inheritance

?Neuropathy, inflammatory demyelinatingMIM #139393

Charcot-Marie-Tooth disease, type 1AMIM #118220

Charcot-Marie-Tooth disease, type 1EMIM #118300

Dejerine-Sottas diseaseMIM #145900

ADAR

Neuropathy, recurrent, with pressure palsiesMIM #162500

Roussy-Levy syndromeMIM #180800

495

ClinVar variants

187

Pathogenic / LP

0.91

pLI score· haploinsufficient

Active trials

Clinical Summary— PMP22

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Gene-Disease Validity (ClinGen)

Charcot-Marie-Tooth disease type 1A · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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.

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ClinVar Variants

187 Pathogenic / Likely Pathogenic· 170 VUS of 495 total submissions

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Clinical Trials

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

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.

0.39LOEUF

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?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.

0.42Z-score

OE missense 0.88 (0.73–1.06)

79 obs / 90.1 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.0.00 (0.00–0.39)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.88 (0.73–1.06)

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.1.06

0≤1.21.6

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

ClinVar Variant Classifications

495 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic154

Likely Pathogenic33

VUS170

Likely Benign101

Benign17

Conflicting20

154

Pathogenic

Likely Pathogenic

170

VUS

101

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	24	8	122	0	154
Likely Pathogenic	9	13	11	0	33
VUS	23	111	35	1	170
Likely Benign	0	3	46	52	101
Benign	0	0	17	0	17
Conflicting	—				20
Total	56	135	231	53	495

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

View in ClinVar →

Protein Context — Lollipop Plot

PMP22 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

PERIPHERAL MYELIN PROTEIN 22; PMP22

MIM #601097 · *

?Neuropathy, inflammatory demyelinating

MIM #139393