Is FKRP p.Val20Ala (c.59T>C) pathogenic?

FKRP p.Val20Ala (c.59T>C) is classified Uncertain significance in FKRP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-12). AlphaMissense: ambiguous (0.5161); Very rare (popmax 0.00687%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with FKRP p.Val20Ala (c.59T>C)?

FKRP p.Val20Ala (c.59T>C) is associated with Cardiovascular phenotype, muscular dystrophy-dystroglycanopathy, type A (ClinVar).

How common is FKRP p.Val20Ala (c.59T>C) in the general population?

FKRP p.Val20Ala (c.59T>C) is very rare (popmax 0.00687%, nfe) (gnomAD).

What do computational predictors say about FKRP p.Val20Ala (c.59T>C)?

AlphaMissense predicts ambiguous (score 0.5161) — an in-silico prediction, not a clinical call.

FKRP p.Val20Ala

c.59T>C · rs750241299 · VCV971112

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5161 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00687%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.5161	ambiguous
REVEL	0.429	indeterminate
SaProt	LLR -6.08	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.5, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,484 bp · p 0.11 · regional, not allelic
Overall
CADD	20.9	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 0.00687% European (non-Finnish) · 81/1,179,176 alleles

Filtering AF 0.00563% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00555% 81/1,458,928 alleles · very rare

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.Val20Ala
Coding: c.59T>C
MANE Select: NM_024301
dbSNP: rs750241299
Type: single nucleotide variant
Location: chr19:46755509 (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

Similar variants

FKRP p.Val20= Likely benign ★ 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
FKRP p.Arg275Cys Pathogenic/Likely pathogenic ★★ same condition
FKRP p.Arg54Gly Likely pathogenic ★★ ⚠ same condition
FKRP p.Asn463Asp 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-val20ala (accessed [today's date]).

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