MSH5

Chr 6AR

mutS homolog 5

Also known as: G7, MUTSH5, NG23, POF13, SPGF74

NCBI Gene: 4439ENSG00000204410UniProt: O43196

This gene encodes a member of the mutS family of proteins that are involved in DNA mismatch repair and meiotic recombination. This protein is similar to a Saccharomyces cerevisiae protein that participates in segregation fidelity and crossing-over events during meiosis. This protein plays a role in promoting ionizing radiation-induced apoptosis. This protein forms hetero-oligomers with another member of this family, mutS homolog 4. Polymorphisms in this gene have been linked to various human diseases, including IgA deficiency, common variable immunodeficiency, and premature ovarian failure. Alternative splicing results multiple transcript variants. Read-through transcription also exists between this gene and the downstream chromosome 6 open reading frame 26 (C6orf26) gene. [provided by RefSeq, Feb 2011]

Primary Disease Associations & Inheritance

?Premature ovarian failure 13MIM #617442
AR
Spermatogenic failure 74MIM #619937
AR
118
ClinVar variants
14
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— MSH5
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
14 Pathogenic / Likely Pathogenic· 86 VUS of 118 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.70LOEUF
pLI 0.000
Z-score 3.30
OE 0.50 (0.37–0.70)
Tolerant

Typical tolerance to LoF variation

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.
1.80Z-score
OE missense 0.77 (0.70–0.84)
367 obs / 477.6 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.0.50 (0.37–0.70)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.77 (0.70–0.84)
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.0.79
0≤1.21.6
LoF obs/exp: 26 / 51.6Missense obs/exp: 367 / 477.6Syn Z: 2.22

ClinVar Variant Classifications

118 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
Likely Pathogenic5
VUS86
Likely Benign10
Benign7
Conflicting1
9
Pathogenic
5
Likely Pathogenic
86
VUS
10
Likely Benign
7
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
1
5
0
9
Likely Pathogenic
0
2
3
0
5
VUS
1
80
5
0
86
Likely Benign
0
6
3
1
10
Benign
0
4
0
3
7
Conflicting
—1
Total493164118

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

View in ClinVar →

Protein Context — Lollipop Plot

MSH5 · 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
MutS HOMOLOG 5; MSH5
MIM #603382 · *

?Premature ovarian failure 13

MIM #617442

Molecular basis of disorder known

Autosomal recessive

Spermatogenic failure 74

MIM #619937

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Next-generation sequencing of 500 POI patients identified novel responsible monogenic and oligogenic variants.
Luo W et al.·J Ovarian Res
2023Cohort
HSF5 Deficiency Causes Male Infertility Involving Spermatogenic Arrest at Meiotic Prophase I in Humans and Mice.
Liu M et al.·Adv Sci (Weinh)
2024
Common variable immunodeficiency.
Bonilla FA et al.·Pediatr Res
2009
[Common variable immunodeficiency].
Morio T·Nihon Rinsho
2012Review
Common variable immunodeficiency in children.
Glocker E et al.·Curr Opin Pediatr
2007Review
Genetic variants in diminished ovarian reserve and premature ovarian insufficiency: implications for assisted reproductive outcomes.
Xu Q et al.·J Assist Reprod Genet
2025
Mouse models for colorectal cancer.
Heyer J et al.·Oncogene
1999Review
Modeling primary ovarian insufficiency-associated loci in C. elegans identifies novel pathogenic allele of MSH5.
Macaisne N et al.·J Assist Reprod Genet
2022Functional
A Homozygous Loss-of-Function Mutation in MSH5 Abolishes MutSγ Axial Loading and Causes Meiotic Arrest in NOA-Affected Individuals.
Gong C et al.·Int J Mol Sci
2022
Role for Msh5 in the regulation of Ig class switch recombination.
Sekine H et al.·Proc Natl Acad Sci U S A
2007
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools