KIRREL3

Chr 11

kirre like nephrin family adhesion molecule 3

Also known as: KIRRE, MRD4, NEPH2, PRO4502

NCBI Gene: 84623ENSG00000149571UniProt: Q8IZU9

KIRREL3 encodes a synaptic cell adhesion molecule that is required for formation of target-specific synapses, particularly hippocampal mossy fiber synapses connecting dentate granule and GABA neurons. Mutations cause autosomal dominant intellectual disability, autism spectrum disorder, and other neurodevelopmental disorders. This gene is highly constrained against loss-of-function variants, indicating that haploinsufficiency is likely not tolerated in the general population.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
8
Pubs (1 yr)
73
P/LP submissions
3%
P/LP missense
0.32
LOEUF· LoF intol.
LOF
Mechanism· predicted
Clinical Summary— KIRREL3
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Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDisputed

Disputed — evidence questions this relationship

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
73 unique Pathogenic / Likely Pathogenic· 123 VUS of 263 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.32LOEUF
pLI 0.970
Z-score 4.75
OE 0.16 (0.09–0.32)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
2.35Z-score
OE missense 0.70 (0.64–0.77)
343 obs / 489.6 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.16 (0.09–0.32)
0≤0.351.4
Missense OE0.70 (0.64–0.77)
0≤0.61.4
Synonymous OE0.94
0≤1.21.6
LoF obs/exp: 6 / 37.3Missense obs/exp: 343 / 489.6Syn Z: 0.74
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
limitedKIRREL3-related intellectual developmental disorderOTHERAD
DN
0.5280th %ile
GOF
0.6248th %ile
LOF
0.65top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.32

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

263 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic68
Likely Pathogenic5
VUS123
Likely Benign43
Benign14
Conflicting2
68
Pathogenic
5
Likely Pathogenic
123
VUS
43
Likely Benign
14
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
68
0
68
Likely Pathogenic
1
2
2
0
5
VUS
1
104
14
4
123
Likely Benign
0
9
5
29
43
Benign
0
3
3
8
14
Conflicting
—2
Total21189241255

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

View in ClinVar →

Protein Context — Lollipop Plot

KIRREL3 · 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

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 4 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Preliminary study on the role and mechanism of KIRREL3 in the development of esophageal squamous cell carcinoma.
Yang B et al.·Pathol Res Pract
2022Functional
KIRREL3-related disorders: a case report confirming the radiological features and expanding the clinical spectrum to a less severe phenotype.
Querzani A et al.·Ital J Pediatr
2023Case report
A Missense De Novo Variant in the CASK-interactor KIRREL3 Gene Leading to Neurodevelopmental Disorder with Mild Cerebellar Hypoplasia.
Ciaccio C et al.·Neuropediatrics
2021
Distortion of the normal function of synaptic cell adhesion molecules by genetic variants as a risk for autism spectrum disorders.
Baig DN et al.·Brain Res Bull
2017Review
Clinical and neuropsychological characterization of Jacobsen syndrome (del11q).
Garriz-Luis A et al.·J Neurodev Disord
2025
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients