What condition is associated with FKRP p.Ser346Pro (c.1036T>C)?

FKRP p.Ser346Pro (c.1036T>C) is associated with autosomal recessive limb-girdle muscular dystrophy type 2I (ClinVar).

How common is FKRP p.Ser346Pro (c.1036T>C) in the general population?

FKRP p.Ser346Pro (c.1036T>C) is absent from gnomAD v4.1 (gnomAD).

How is FKRP-related limb-girdle muscular dystrophy R9 inherited?

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

What do computational predictors say about FKRP p.Ser346Pro (c.1036T>C)?

AlphaMissense predicts likely pathogenic (score 0.9858) — an in-silico prediction, not a clinical call.

FKRP p.Ser346Pro

Q: Is FKRP p.Ser346Pro (c.1036T>C) pathogenic?

FKRP p.Ser346Pro (c.1036T>C) is classified Likely pathogenic in FKRP (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9858); Absent from gnomAD v4.1; Associated with autosomal recessive limb-girdle muscular dystrophy type 2I.

c.1036T>C · rs753811189 · VCV487485

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9858 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2I

Computational evidence

Protein change
AlphaMissense	0.9858	likely pathogenic ✓ concordant with ClinVar · top 7% in FKRP
REVEL	0.813	moderately pathogenic-leaning
SaProt	LLR -13.12	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5	GERP 0.29, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,484 bp · p 0.11 · regional, not allelic
Overall
CADD	26.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FKRP
Protein: p.Ser346Pro
Coding: c.1036T>C
MANE Select: NM_024301
dbSNP: rs753811189
Type: single nucleotide variant
Location: chr19:46756486 (GRCh38)
Gene constraint: LOEUF 1.543 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.08 · 8 PDB
Residue 346: an α-helix

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

Disease context

autosomal recessive limb-girdle muscular dystrophy type 2I — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For FKRP-related limb-girdle muscular dystrophy R9 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

FKRP p.Ser346= Likely benign ★★ same residue
FKRP p.Ser346Leu Uncertain significance ★ ⚠ same residue
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

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-ser346pro (accessed [today's date]).

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