FKRP

Chr 19AR

fukutin related protein

Also known as: FKTR, LGMD2I, LGMDR9, MDC1C, MDDGA5, MDDGB5, MDDGC5

NCBI Gene: 79147ENSG00000181027UniProt: Q9H9S5

This gene encodes a protein which is targeted to the medial Golgi apparatus and is necessary for posttranslational modification of dystroglycan. Mutations in this gene have been associated with congenital muscular dystrophy, cognitive disability, and cerebellar cysts. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Oct 2008]

Primary Disease Associations & Inheritance

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 5MIM #613153
AR
Muscular dystrophy-dystroglycanopathy (congenital with or without impaired intellectual development), type B, 5MIM #606612
AR
Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 5MIM #607155
AR
598
ClinVar variants
101
Pathogenic / LP
0.00
pLI score
3
Active trials
Clinical Summary— FKRP
🧬
Gene-Disease Validity (ClinGen)
myopathy caused by variation in FKRP · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
101 Pathogenic / Likely Pathogenic· 246 VUS of 598 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available

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.
1.32LOEUF
pLI 0.000
Z-score 0.78
OE 0.76 (0.46–1.32)
Tolerant

Highly tolerant — LoF variants common in population

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.
1.85Z-score
OE missense 0.71 (0.64–0.79)
230 obs / 323.6 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.0.76 (0.46–1.32)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.71 (0.64–0.79)
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: 9 / 11.9Missense obs/exp: 230 / 323.6Syn Z: 2.05

ClinVar Variant Classifications

598 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic40
Likely Pathogenic61
VUS246
Likely Benign242
Conflicting9
40
Pathogenic
61
Likely Pathogenic
246
VUS
242
Likely Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
21
6
13
0
40
Likely Pathogenic
16
28
17
0
61
VUS
3
230
9
4
246
Likely Benign
0
1
3
238
242
Benign
0
0
0
0
0
Conflicting
—9
Total4026542242598

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

View in ClinVar →

Protein Context — Lollipop Plot

FKRP · protein map & ClinVar variants

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

Gene2Phenotype Curations

FKRP-related congenital alpha-dystroglycanopathy with brain and eye anomalies

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 5

MIM #613153

Molecular basis of disorder known

Autosomal recessive

Muscular dystrophy-dystroglycanopathy (congenital with or without impaired intellectual development), type B, 5

MIM #606612

Molecular basis of disorder known

Autosomal recessive

Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 5

MIM #607155

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — FKRP
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The Limb-Girdle Muscular Dystrophies.
Johnson NE et al.·Continuum (Minneap Minn)
2022Review
Genetic variations and clinical spectrum of dystroglycanopathy in a large cohort of Chinese patients.
Song D et al.·Clin Genet
2021Cohort
Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review.
Conte F et al.·Int J Mol Sci
2023Review
Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients.
Ten Dam L et al.·Clin Genet
2019Cohort
Phenotypic Spectrum of α-Dystroglycanopathies Associated With the c.919T>a Variant in the FKRP Gene in Humans and Mice.
Brown SC et al.·J Neuropathol Exp Neurol
2020Review
Saturation mutagenesis-reinforced functional assays for disease-related genes.
Ma K et al.·Cell
2024Functional
NAD+ improves neuromuscular development in a zebrafish model of FKRP-associated dystroglycanopathy.
Bailey EC et al.·Skelet Muscle
2019Review
FKRP directed fibronectin glycosylation: A novel mechanism giving insights into muscular dystrophies?
Boyd A et al.·Bioessays
2022Review
Break Down of the Complexity and Inconsistency Between Levels of Matriglycan and Disease Phenotype in FKRP-Related Dystroglycanopathies: A Review and Model of Interpretation.
Lu QL et al.·J Neuromuscul Dis
2024Review
Prospective observational study of FKRP-related limb-girdle muscular dystrophy R9: A GRASP consortium study.
Alfano LN et al.·Ann Clin Transl Neurol
2025
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
Limb Girdle Muscular DystrophyLimb-Girdle Muscular Dystrophy Type 2LGMD2I

A Study to Evaluate the Safety of AB-1003 (Previously LION-101) in Subjects With Genetic Confirmation of LGMD2I/R9 (Part1)

RECRUITING
NCT05230459Phase PHASE1, PHASE2AskBio IncStarted 2023-05-15
AB-1003 dose level 1AB-1003 dose level 2Placebo
Muscular Dystrophy

Clinical Trial Readiness for the Dystroglycanopathies

RECRUITING
NCT00313677Katherine MathewsStarted 2006-04
LGMDR9

ATA-100 (Formerly GNT0006) Gene Therapy Trial in Patients With LGMDR9

ACTIVE NOT RECRUITING
NCT05224505Phase PHASE1Atamyo TherapeuticsStarted 2022-09-01
ATA-100 (AAV9 encoding FKRP gene)

External Resources

Links to major genomics databases and tools