Is FKRP p.Ser69Pro (c.205T>C) pathogenic?

FKRP p.Ser69Pro (c.205T>C) is classified Conflicting classifications of pathogenicity in FKRP (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2023-11-05). AlphaMissense: likely pathogenic (0.9387); Very rare (popmax 0.00268%, afr); Associated with Cardiovascular phenotype.

How common is FKRP p.Ser69Pro (c.205T>C) in the general population?

FKRP p.Ser69Pro (c.205T>C) is very rare (popmax 0.00268%, afr) (gnomAD).

What do computational predictors say about FKRP p.Ser69Pro (c.205T>C)?

AlphaMissense predicts likely pathogenic (score 0.9387) — an in-silico prediction, not a clinical call.

FKRP p.Ser69Pro

Q: What condition is associated with FKRP p.Ser69Pro (c.205T>C)?

FKRP p.Ser69Pro (c.205T>C) is associated with Cardiovascular phenotype, muscular dystrophy-dystroglycanopathy, type A, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 (ClinVar).

c.205T>C · rs990847012 · VCV999725

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9387 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9387	likely pathogenic
REVEL	0.812	moderately pathogenic-leaning
SaProt	LLR -17.46	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 7.8	GERP 1.4, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,484 bp · p 0.11 · regional, not allelic
Overall
CADD	25.9	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 0.00268% African / African-American · 2/74,686 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00131% 2/152,110 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.Ser69Pro
Coding: c.205T>C
MANE Select: NM_024301
dbSNP: rs990847012
Type: single nucleotide variant
Location: chr19:46755655 (GRCh38)
Gene constraint: LOEUF 1.543 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.08 · 8 PDB
Residue 69: an α-helix

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 muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 muscular dystrophy-dystroglycanopathy type B5 autosomal recessive limb-girdle muscular dystrophy type 2I muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5

Similar variants

FKRP p.Ser69Phe Uncertain significance ★★ ⚠ same residue
FKRP p.Ser69Ala Uncertain significance ★ ⚠ same residue
FKRP p.Ser69del Pathogenic/Likely 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

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-ser69pro (accessed [today's date]).

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