Is FKRP p.Ala397Val (c.1190C>T) pathogenic?

FKRP p.Ala397Val (c.1190C>T) is classified Uncertain significance in FKRP (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-01-06). AlphaMissense: likely pathogenic (0.9586); Very rare (popmax 0.00167%, amr); Associated with muscular dystrophy-dystroglycanopathy, type A.

What condition is associated with FKRP p.Ala397Val (c.1190C>T)?

FKRP p.Ala397Val (c.1190C>T) is associated with muscular dystrophy-dystroglycanopathy, type A, autosomal recessive limb-girdle muscular dystrophy type 2I (ClinVar).

How common is FKRP p.Ala397Val (c.1190C>T) in the general population?

FKRP p.Ala397Val (c.1190C>T) is very rare (popmax 0.00167%, amr) (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.Ala397Val (c.1190C>T)?

AlphaMissense predicts likely pathogenic (score 0.9586) — an in-silico prediction, not a clinical call.

FKRP p.Ala397Val

c.1190C>T · rs767570224 · VCV435192

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9586 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

muscular dystrophy-dystroglycanopathy, type A

Computational evidence

Protein change
AlphaMissense	0.9586	likely pathogenic
REVEL	0.85	moderately pathogenic-leaning
SaProt	LLR -12.90	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 7.5	GERP 1.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,484 bp · p 0.11 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,834 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000682% 11/1,612,976 alleles · very rare exomes 9/1,460,820 · genomes 2/152,156 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,834
Remaining individualsnot grpmax-eligible	0.0016%	62,432
European (non-Finnish)	0.000763%	131,082

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.Ala397Val
Coding: c.1190C>T
MANE Select: NM_024301
dbSNP: rs767570224
Type: single nucleotide variant
Location: chr19:46756640 (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

muscular dystrophy-dystroglycanopathy, type A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: 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.Ala397= Likely benign ★ same residue
FKRP p.Ala397fs Pathogenic ★★ 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

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-ala397val (accessed [today's date]).

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