FKRP

Chr 19AR

fukutin related protein

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

NCBI Gene: 79147 ENSG00000181027 UniProt: Q9H9S5 OMIM: 606596

The protein is targeted to the medial Golgi apparatus and is necessary for posttranslational modification of dystroglycan. Mutations cause autosomal recessive muscular dystrophy-dystroglycanopathy with a spectrum ranging from severe congenital forms with brain and eye anomalies to milder limb-girdle presentations, often with cognitive disability and cerebellar cysts. The pathogenicity results from defective dystroglycan modification leading to impaired muscle membrane stability and brain development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 5MIM #613153

Muscular dystrophy-dystroglycanopathy (congenital with or without impaired intellectual development), type B, 5MIM #606612

Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 5MIM #607155

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · myopathy caused by variation in FKRP · AR · ClinGen 2024
Definitive · autosomal recessive limb-girdle muscular dystrophy type 2I · AR · Laboratory for Molecular Medicine
Definitive · muscular dystrophy-dystroglycanopathy type B5 · AR · Myriad Women's Health
Definitive · muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 · AR · G2P

+6 more curated pairs

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.32

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — FKRP

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

1.85Z-score

OE missense 0.71 (0.64–0.79)

230 obs / 323.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.76 (0.46–1.32)

0≤0.351.4

Missense OE?0.71 (0.64–0.79)

0≤0.61.4

Synonymous OE?0.79

0≤1.21.6

LoF obs/exp: 9 / 11.9Missense obs/exp: 230 / 323.6Syn Z: 2.05

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 93

827 rare PASS variants

Rare truncating (LoF)

1 in 2,300

83 rare PASS variants

Rare synonymous (reference)

1 in 120

385 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FKRP. 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 170	1 in 2,600
South Asian	~43k	1 in 110	1 in 3,300
Remaining (unassigned)	~30k	1 in 85	1 in 2,500
European (Finnish)	~27k	1 in 180	1 in 790
Admixed American	~22k	1 in 60	≈ 1 in 4,900
African / African American	~21k	1 in 68	1 in 2,100
East Asian	~20k	1 in 78	1 in 800
Ashkenazi Jewish	~13k	1 in 140	≈ 1 in 6,000
Middle Eastern	~2,884	1 in 82	≈ 1 in 850

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): All 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓