Is FKRP p.Ala157Pro (c.469G>C) pathogenic?

FKRP p.Ala157Pro (c.469G>C) is classified Pathogenic/Likely pathogenic in FKRP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-29). AlphaMissense: likely pathogenic (0.9779); Very rare (popmax 0.00131%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy.

How common is FKRP p.Ala157Pro (c.469G>C) in the general population?

FKRP p.Ala157Pro (c.469G>C) is very rare (popmax 0.00131%, nfe) (gnomAD).

What do computational predictors say about FKRP p.Ala157Pro (c.469G>C)?

AlphaMissense predicts likely pathogenic (score 0.9779) — an in-silico prediction, not a clinical call.

FKRP p.Ala157Pro

Q: What condition is associated with FKRP p.Ala157Pro (c.469G>C)?

FKRP p.Ala157Pro (c.469G>C) is associated with autosomal recessive limb-girdle muscular dystrophy, muscular dystrophy-dystroglycanopathy, type A, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 (ClinVar).

c.469G>C · rs727502842 · VCV2577157

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9779 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00131%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy

Computational evidence

Protein change
AlphaMissense	0.9779	likely pathogenic ✓ concordant with ClinVar · top 10% in FKRP
REVEL	0.655	pathogenic-leaning
SaProt	LLR -16.18	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,484 bp · p 0.11 · regional, not allelic
Overall
CADD	22.7	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 0.00131% European (non-Finnish) · 15/1,142,960 alleles

Filtering AF 0.000788% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000625%

Overall 0.00109% 15/1,375,752 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.Ala157Pro
Coding: c.469G>C
MANE Select: NM_024301
dbSNP: rs727502842
Type: single nucleotide variant
Location: chr19:46755919 (GRCh38)
Gene constraint: LOEUF 1.543 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.08 · 8 PDB
Residue 157: a β-strand

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

Disease context

autosomal recessive limb-girdle muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: muscular dystrophy-dystroglycanopathy, type A muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5

Similar variants

FKRP p.Ala157= Likely benign ★★ same residue
FKRP p.Ala157Gly Uncertain significance ★ ⚠ same residue
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-ala157pro (accessed [today's date]).

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