Is FKRP p.Pro316Ser (c.946C>T) pathogenic?

FKRP p.Pro316Ser (c.946C>T) is classified Conflicting classifications of pathogenicity in FKRP (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-05). AlphaMissense: likely pathogenic (0.8966); Very rare (popmax 0.0019%, amr); Associated with muscular dystrophy-dystroglycanopathy, type A.

How common is FKRP p.Pro316Ser (c.946C>T) in the general population?

FKRP p.Pro316Ser (c.946C>T) is very rare (popmax 0.0019%, 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.Pro316Ser (c.946C>T)?

AlphaMissense predicts likely pathogenic (score 0.8966) — an in-silico prediction, not a clinical call.

FKRP p.Pro316Ser

Q: What condition is associated with FKRP p.Pro316Ser (c.946C>T)?

FKRP p.Pro316Ser (c.946C>T) is associated with muscular dystrophy-dystroglycanopathy, type A, autosomal recessive limb-girdle muscular dystrophy type 2I, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 (ClinVar).

c.946C>T · rs28937901 · VCV197346

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8966 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0019%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

muscular dystrophy-dystroglycanopathy, type A

Computational evidence

Protein change
AlphaMissense	0.8966	likely pathogenic
REVEL	0.902	moderately pathogenic-leaning
SaProt	LLR -8.77	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,484 bp · p 0.11 · regional, not allelic
Overall
CADD	24.9	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 0.0019% Admixed American · 1/52,612 alleles

Filtering AF 0.000778% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000617%

Overall 0.00115% 18/1,569,070 alleles · very rare exomes 18/1,416,968 · genomes 0/152,102 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00329%	30,383
Admixed Americangrpmax	0.0019%	52,612
European (non-Finnish)	0.0013%	77,219

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro316Ser
Coding: c.946C>T
MANE Select: NM_024301
dbSNP: rs28937901
Type: single nucleotide variant
Location: chr19:46756396 (GRCh38)
Gene constraint: LOEUF 1.543 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.08 · 8 PDB
Residue 316: the 'zinc finger loop' region; a UniProt-annotated variant site (in mddgb5 and mddgc5); a UniProt-annotated variant site (in mddgc5); an α-helix

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 muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5

For Walker-Warburg syndrome (Orphanet):

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

Similar variants

FKRP p.Pro316Arg Pathogenic/Likely pathogenic ★★ same residue
FKRP p.Pro316Thr Pathogenic/Likely pathogenic ★★ ⚠ same residue
FKRP p.Pro316= Likely benign ★★ same residue
FKRP p.Pro316Ala Likely pathogenic ★ ⚠ same residue
FKRP p.Pro316fs 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

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-pro316ser (accessed [today's date]).

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