Is FKRP p.Arg2Trp (c.4C>T) pathogenic?

FKRP p.Arg2Trp (c.4C>T) is classified Uncertain significance in FKRP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-15). AlphaMissense: ambiguous (0.409); Very rare (popmax 0.00127%, nfe); Associated with Cardiovascular phenotype.

How common is FKRP p.Arg2Trp (c.4C>T) in the general population?

FKRP p.Arg2Trp (c.4C>T) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about FKRP p.Arg2Trp (c.4C>T)?

AlphaMissense predicts ambiguous (score 0.409) — an in-silico prediction, not a clinical call.

FKRP p.Arg2Trp

Q: What condition is associated with FKRP p.Arg2Trp (c.4C>T)?

FKRP p.Arg2Trp (c.4C>T) is associated with Cardiovascular phenotype, muscular dystrophy-dystroglycanopathy, type A, autosomal recessive limb-girdle muscular dystrophy type 2I (ClinVar).

c.4C>T · rs748272589 · VCV664545

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.409 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.409	ambiguous
REVEL	0.801	moderately pathogenic-leaning
SaProt	LLR -10.39	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP 1.5, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,484 bp · p 0.11 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00127% European (non-Finnish) · 15/1,178,866 alleles

Filtering AF 0.000764% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000606%

Overall 0.000935% 15/1,604,636 alleles · very rare exomes 13/1,452,442 · genomes 2/152,194 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FKRP
Protein: p.Arg2Trp
Coding: c.4C>T
MANE Select: NM_024301
dbSNP: rs748272589
Type: single nucleotide variant
Location: chr19:46755454 (GRCh38)
Gene constraint: LOEUF 1.543 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.08 · 8 PDB

Full FKRP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: muscular dystrophy-dystroglycanopathy, type A autosomal recessive limb-girdle muscular dystrophy type 2I

Similar variants

FKRP p.Arg2Gln Uncertain significance ★ ⚠ same residue
FKRP p.Arg2Leu Uncertain significance ★ ⚠ same residue
FKRP p.Arg2= Likely benign ★ same residue
STRN4 p.Met2Leu Uncertain significance ★ ⚠ same residue
FKRP p.Ala157Pro Pathogenic/Likely pathogenic ★★ same condition
FKRP p.Ala321Glu Pathogenic/Likely pathogenic ★★ ⚠ same condition
FKRP p.Ala455Asp Pathogenic ★★ same condition
FKRP p.Arg176Ter Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/fkrp-p-arg2trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown