# NM_024301.5(FKRP):c.75G>T (p.Ser25=)

https://sugi.bio/variant/fkrp-p-ser25

## Summary

**FKRP p.Ser25= (c.75G>T)** is classified **Likely benign** in FKRP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-08). Very rare (popmax 0.0011%, sas); Associated with muscular dystrophy-dystroglycanopathy, type A.

**At a glance:** Likely benign · review: Single submitter · rsID rs1555738032 · 1 submitter · 1 linked condition · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the FKRP gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to muscular dystrophy-dystroglycanopathy, type A.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Antenatal, Infancy, Neonatal |
| Prevalence | <1 / 1 000 000 (United Kingdom) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | FKRP is a diagnostic-grade gene on 21 Genomics England panels |

**Commonly reported features of Walker-Warburg syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Areflexia — Very frequent (99-80%)
- Pachygyria — Very frequent (99-80%)
- Cerebellar hypoplasia — Very frequent (99-80%)
- Muscle weakness — Very frequent (99-80%)
- Specific learning disability — Very frequent (99-80%)
- Lissencephaly — Very frequent (99-80%)
- Aplasia/Hypoplasia involving the skeletal musculature — Very frequent (99-80%)
- Ventriculomegaly — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002599/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FKRP](https://sugi.bio/atlas/gene/FKRP/) |
| Protein change (HGVS p.) | p.Ser25= |
| Coding change (HGVS c.) | c.75G>T |
| MANE Select transcript | [NM_024301](https://www.ncbi.nlm.nih.gov/nuccore/NM_024301) |
| dbSNP | [rs1555738032](https://www.ncbi.nlm.nih.gov/snp/rs1555738032/) |
| Variant type | single nucleotide variant |
| Location | chr19:46755525-46755525 (GRCh38) |
| ClinVar | [VCV1610177](https://www.ncbi.nlm.nih.gov/clinvar/variation/1610177/) |

**All HGVS expressions:** `LRG_761:g.14480G>T`, `LRG_761t1:c.75G>T`, `NC_000019.10:g.46755525G>T`, `NC_000019.9:g.47258782G>T`, `NG_008898.2:g.14480G>T`, `NM_001039885.3:c.75G>T`, `NM_024301.5:c.75G>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.21) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -7.457, GERP -2.91 — fast-evolving / accelerated position
- CADD: **PHRED 1.919**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · 1/90,642 in the highest group · 1/1,610,008 alleles overall — very rare (popmax 0.0011%, sas).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**FKRP** population constraint: LOEUF 1.543, pLI 6.1822e-10, missense-Z -2.4908. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **myopathy caused by variation in FKRP** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 94.08, 86% of residues very-high.

**8 experimental structure(s)** (PDB): [6KAJ](https://www.rcsb.org/structure/6KAJ), [6KAK](https://www.rcsb.org/structure/6KAK), [6KAL](https://www.rcsb.org/structure/6KAL), [6KAM](https://www.rcsb.org/structure/6KAM), [6KAN](https://www.rcsb.org/structure/6KAN), [6L7S](https://www.rcsb.org/structure/6L7S).

## What this gene does {#gene-function}

*Describes the biological roles of FKRP (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** FKRP's established molecular role includes phosphotransferase activity, for other substituted phosphate groups.


### Pathways affected {#pathways}

FKRP participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Matriglycan biosynthesis on DAG1](https://reactome.org/content/detail/R-HSA-9939291) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** phosphotransferase activity, for other substituted phosphate groups, identical protein binding.

**Biological process:** protein O-linked glycosylation via mannose, protein tetramerization.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-10-08.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2021-10-08 |

## Associated conditions {#conditions}

[muscular dystrophy-dystroglycanopathy, type A](https://sugi.bio/atlas/disease/muscular-dystrophy-dystroglycanopathy-type-a/).

**Reported phenotype names (ClinVar):** Walker-Warburg congenital muscular dystrophy, Muscular dystrophy-dystroglycanopathy, type A, Walker-Warburg syndrome.

## Same-residue context {#hotspot}

Residue **25** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [FKRP p.Ser25fs](/variant/fkrp-p-ser25fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related FKRP variant pages (same residue, condition, or type): [FKRP p.Ala157Pro](/variant/fkrp-p-ala157pro), [FKRP p.Ala321Glu](/variant/fkrp-p-ala321glu), [FKRP p.Ala455Asp](/variant/fkrp-p-ala455asp), [FKRP p.Arg176Ter](/variant/fkrp-p-arg176ter), [FKRP p.Arg275Cys](/variant/fkrp-p-arg275cys), [FKRP p.Arg54Gly](/variant/fkrp-p-arg54gly), [FKRP p.Asn463Asp](/variant/fkrp-p-asn463asp), [FKRP p.Gln105Ter](/variant/fkrp-p-gln105ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1610177). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*