MPHOSPH8

Chr 13

M-phase phosphoprotein 8

Also known as: HSMPP8, TWA3, mpp8

NCBI Gene: 54737 ENSG00000196199 UniProt: Q99549

MPHOSPH8 encodes a heterochromatin component that recognizes methylated histone H3K9 and promotes epigenetic gene silencing through recruitment of DNA methyltransferases and chromatin remodeling complexes, particularly silencing transposable elements and interferon-stimulated genes. Mutations cause neurodevelopmental disorder with epilepsy, spasticity, and brain abnormalities, inherited in an autosomal recessive pattern. The gene shows high constraint against loss-of-function variants (LOEUF 0.525), consistent with its critical role in chromatin regulation and neurodevelopment.

ResearchSummary from RefSeq, UniProt

Enables chromatin binding activity and histone H3K9me2/3 reader activity. Involved in negative regulation of gene expression via chromosomal CpG island methylation; negative regulation of type I interferon production; and transposable element silencing by heterochromatin formation. Located in cytoplasm; heterochromatin; and nucleoplasm. Part of HUSH complex; HUSH2 complex; and nucleosome. Is active in chromatin and nucleus. [provided by Alliance of Genome Resources, Jun 2026]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.53

LOEUF

—

Mechanism

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.53LOEUF

pLI 0.001

Z-score 3.81

OE 0.32 (0.21–0.53)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.08Z-score

OE missense 0.85 (0.79–0.93)

377 obs / 441.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.32 (0.21–0.53)

0≤0.351.4

Missense OE?0.85 (0.79–0.93)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 12 / 37.0Missense obs/exp: 377 / 441.1Syn Z: -0.84

Background carrier burden — how many people carry a rare variant somewhere in MPHOSPH8?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 59

1,043 rare PASS variants

Rare truncating (LoF)

1 in 1,500

156 rare PASS variants

Rare synonymous (reference)

1 in 110

417 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MPHOSPH8. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 66	1 in 1,700
South Asian	~43k	1 in 61	1 in 1,900
Remaining (unassigned)	~30k	1 in 50	1 in 680
European (Finnish)	~27k	1 in 270	≈ 1 in 27,000
Admixed American	~22k	1 in 60	1 in 1,100
African / African American	~21k	1 in 55	1 in 1,200
East Asian	~20k	1 in 70	1 in 440
Ashkenazi Jewish	~13k	1 in 260	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 81	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 13 of 14 coding exons well covered in gnomAD exomes; exon 4 marginal. Genomes: all 14.? see exons ↓