Is FKRP p.Ala227Pro (c.679G>C) pathogenic?

FKRP p.Ala227Pro (c.679G>C) is classified Conflicting classifications of pathogenicity in FKRP (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-20). AlphaMissense: likely pathogenic (0.9071); Very rare (popmax 0.00764%, sas); Associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 10.

What condition is associated with FKRP p.Ala227Pro (c.679G>C)?

FKRP p.Ala227Pro (c.679G>C) is associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 10, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4, autosomal recessive limb-girdle muscular dystrophy type 2I (ClinVar).

How common is FKRP p.Ala227Pro (c.679G>C) in the general population?

FKRP p.Ala227Pro (c.679G>C) is very rare (popmax 0.00764%, sas) (gnomAD).

How is Walker-Warburg syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FKRP p.Ala227Pro (c.679G>C)?

AlphaMissense predicts likely pathogenic (score 0.9071) — an in-silico prediction, not a clinical call.

FKRP p.Ala227Pro

c.679G>C · rs775681117 · VCV430845

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9071 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00764%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 10

Computational evidence

Protein change
AlphaMissense	0.9071	likely pathogenic
REVEL	0.577	indeterminate
SaProt	LLR -6.57	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -1.9, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,484 bp · p 0.11 · regional, not allelic
Overall
CADD	12.84	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 0.00764% South Asian · 6/78,550 alleles

Filtering AF 0.00324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0022%

Overall 0.000467% 7/1,500,282 alleles · very rare exomes 7/1,348,248 · genomes 0/152,034 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00764%	13,092
East Asian	0.00266%	37,632

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.Ala227Pro
Coding: c.679G>C
MANE Select: NM_024301
dbSNP: rs775681117
Type: single nucleotide variant
Location: chr19:46756129 (GRCh38)
Gene constraint: LOEUF 1.543 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.08 · 8 PDB
Residue 227: an α-helix

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

Disease context

muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 10 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 autosomal recessive limb-girdle muscular dystrophy type 2I

For Walker-Warburg syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal
Prevalence: <1 / 1 000 000 (United Kingdom)

Similar variants

FKRP p.Ala455Asp Pathogenic ★★ same condition
FKRP p.Arg176Ter Pathogenic/Likely pathogenic ★★ same condition
FKRP p.Arg275Cys Pathogenic/Likely pathogenic ★★ same condition
FKRP p.Asn463Asp Pathogenic/Likely pathogenic ★★ same condition
FKRP p.Gln105Ter Pathogenic/Likely pathogenic ★★ same condition
FKRP p.Gln406Ter Pathogenic/Likely pathogenic ★★ same condition
FKRP p.Gln72Ter Pathogenic/Likely pathogenic ★★ same condition
FKRP p.Gln77Ter 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-ala227pro (accessed [today's date]).

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