MSH4

Chr 1AR

mutS homolog 4

Also known as: ASG, POF20, SPGF2

This gene encodes a member of the DNA mismatch repair mutS family. This member is a meiosis-specific protein that is not involved in DNA mismatch correction, but is required for reciprocal recombination and proper segregation of homologous chromosomes at meiosis I. This protein and MSH5 form a heterodimer which binds uniquely to a Holliday Junction and its developmental progenitor, thus provoking ADP-ATP exchange, and stabilizing the interaction between parental chromosomes during meiosis double-stranded break repair. [provided by RefSeq, Aug 2011]

Primary Disease Associations & Inheritance

Premature ovarian failure 20MIM #619938
AR
Spermatogenic failure 2MIM #108420
AR
0
Active trials
17
Pubs (1 yr)
0
P/LP submissions
P/LP missense
0.99
LOEUF
DN
Mechanism· predicted
Clinical SummaryMSH4
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint
0.99LOEUF
pLI 0.000
Z-score 1.61
OE 0.74 (0.560.99)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.81Z-score
OE missense 0.89 (0.820.97)
413 obs / 461.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.74 (0.560.99)
00.351.4
Missense OE0.89 (0.820.97)
00.61.4
Synonymous OE0.81
01.21.6
LoF obs/exp: 34 / 45.8Missense obs/exp: 413 / 461.8Syn Z: 1.97
DN
0.6841th %ile
GOF
0.3987th %ile
LOF
0.4136th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

MSH4 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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