Is FKRP p.Pro451Ser (c.1351C>T) pathogenic?

FKRP p.Pro451Ser (c.1351C>T) is classified Uncertain significance in FKRP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-10). AlphaMissense: likely benign (0.0954); Very rare (popmax 8.52e-05%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with FKRP p.Pro451Ser (c.1351C>T)?

FKRP p.Pro451Ser (c.1351C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is FKRP p.Pro451Ser (c.1351C>T) in the general population?

FKRP p.Pro451Ser (c.1351C>T) is very rare (popmax 8.52e-05%, nfe) (gnomAD).

What do computational predictors say about FKRP p.Pro451Ser (c.1351C>T)?

AlphaMissense predicts likely benign (score 0.0954) — an in-silico prediction, not a clinical call.

FKRP p.Pro451Ser

c.1351C>T · rs2513999386 · VCV3227826

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0954 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.52e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0954	likely benign
REVEL	0.545	indeterminate
SaProt	LLR -7.32	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 1.4, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,484 bp · p 0.11 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 8.52e-05% European (non-Finnish) · 1/1,174,256 alleles

Overall 6.9e-05% 1/1,448,476 alleles · very rare

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.Pro451Ser
Coding: c.1351C>T
MANE Select: NM_024301
dbSNP: rs2513999386
Type: single nucleotide variant
Location: chr19:46756801 (GRCh38)
Gene constraint: LOEUF 1.543 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.08 · 8 PDB
Residue 451: 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

Similar variants

FKRP p.Pro451Leu Uncertain significance ★★ ⚠ same residue
FKRP p.Pro451= Likely benign ★★ same residue
FKRP p.Gln460Ter Pathogenic/Likely pathogenic ★★ same condition
FKRP p.Gln77Ter Pathogenic/Likely pathogenic ★★ same condition
FKRP p.Pro462Ser Pathogenic/Likely pathogenic ★★ same condition
FKRP p.Pro89Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
FKRP c.-2C>A Uncertain significance ★★ same condition
FKRP p.Ala102Glu Uncertain significance ★★ ⚠ 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-pro451ser (accessed [today's date]).

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