CHMP1A

Chr 16AR

charged multivesicular body protein 1A

Also known as: CHMP1, PCH8, PCOLN3, PRSM1, VPS46-1, VPS46A

NCBI Gene: 5119 ENSG00000131165 UniProt: Q9HD42 OMIM: 164010

The CHMP1A protein is a component of the ESCRT-III complex that mediates endosomal cargo sorting into multivesicular bodies for lysosomal degradation and functions in cytokinesis and chromosome condensation. Mutations cause pontocerebellar hypoplasia type 8, a severe neurodevelopmental disorder affecting the brainstem and cerebellum, inherited in an autosomal recessive pattern. The gene shows low constraint against loss-of-function variants, consistent with recessive inheritance where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the CHMP/Chmp family of proteins which are involved in multivesicular body sorting of proteins to the interiors of lysosomes. The initial prediction of the protein sequence encoded by this gene suggested that the encoded protein was a metallopeptidase. The nomenclature has been updated recently to reflect the correct biological function of this encoded protein. Several transcripts encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.181 OMIM phenotype

Clinical Summary— CHMP1A

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 87 VUS of 271 total submissions

💊

Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.18LOEUF

pLI 0.000

Z-score 1.16

OE 0.63 (0.36–1.18)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.76Z-score

OE missense 0.81 (0.69–0.95)

102 obs / 126.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.63 (0.36–1.18)

0≤0.351.4

Missense OE?0.81 (0.69–0.95)

0≤0.61.4

Synonymous OE?1.22

0≤1.21.6

LoF obs/exp: 7 / 11.2Missense obs/exp: 102 / 126.0Syn Z: -1.31

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCHMP1A-related pontocerebellar hypoplasia and microcephalyLOFAR

This gene — mechanism propensity

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

0.86top 5%

GOF

0.74top 25%

LOF

0.2092th %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

271 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic4

VUS87

Likely Benign108

Benign39

Conflicting20

Pathogenic

Likely Pathogenic

VUS

108

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	3	0	1	0	4
VUS	1	80	6	0	87
Likely Benign	6	24	77	1	108
Benign	0	3	35	1	39
Conflicting	—				20
Total	11	107	119	2	259

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

View in ClinVar →

40 pathogenic / likely-pathogenic (of 78) ClinVar copy-number / structural variants overlap CHMP1A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →