Is FKRP p.Pro462Ser (c.1384C>T) pathogenic?

FKRP p.Pro462Ser (c.1384C>T) is classified Pathogenic/Likely pathogenic in FKRP (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-07-22). AlphaMissense: likely pathogenic (0.9893); Very rare (popmax 0.00145%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with FKRP p.Pro462Ser (c.1384C>T)?

FKRP p.Pro462Ser (c.1384C>T) is associated with Cardiovascular phenotype, muscular dystrophy-dystroglycanopathy, type A, autosomal recessive limb-girdle muscular dystrophy type 2I (ClinVar).

How common is FKRP p.Pro462Ser (c.1384C>T) in the general population?

FKRP p.Pro462Ser (c.1384C>T) is very rare (popmax 0.00145%, nfe) (gnomAD).

What do computational predictors say about FKRP p.Pro462Ser (c.1384C>T)?

AlphaMissense predicts likely pathogenic (score 0.9893) — an in-silico prediction, not a clinical call.

FKRP p.Pro462Ser

c.1384C>T · rs768606230 · VCV555554

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00145%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9893	likely pathogenic ✓ concordant with ClinVar · top 5% in FKRP
REVEL	0.925	moderately pathogenic-leaning
SaProt	LLR -15.09	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 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,484 bp · p 0.11 · regional, not allelic
Overall
CADD	27.4	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 0.00145% European (non-Finnish) · 17/1,174,252 alleles

Filtering AF 0.000882% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000721%

Overall 0.00119% 19/1,600,784 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00323%	30,982
European (non-Finnish)grpmax	0.00145%	69,074

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.Pro462Ser
Coding: c.1384C>T
MANE Select: NM_024301
dbSNP: rs768606230
Type: single nucleotide variant
Location: chr19:46756834 (GRCh38)
Gene constraint: LOEUF 1.543 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.08 · 8 PDB
Residue 462: a UniProt-annotated variant site (in mddgc5); a β-strand

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: muscular dystrophy-dystroglycanopathy, type A autosomal recessive limb-girdle muscular dystrophy type 2I autosomal recessive limb-girdle muscular dystrophy

Similar variants

FKRP p.Pro462Arg Likely pathogenic ★ same residue
FKRP p.Pro462Leu Likely pathogenic ★ same residue
FKRP p.Pro462= Likely benign ★ same residue
FKRP p.Pro462Thr Uncertain significance ★ ⚠ 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

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-pro462ser (accessed [today's date]).

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