Is FKRP p.Pro89Ser (c.265C>T) pathogenic?

FKRP p.Pro89Ser (c.265C>T) is classified Likely pathogenic in FKRP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-01). AlphaMissense: likely pathogenic (0.9648); Very rare (popmax 0.00172%, amr); Associated with FKRP-related disorder.

How common is FKRP p.Pro89Ser (c.265C>T) in the general population?

FKRP p.Pro89Ser (c.265C>T) is very rare (popmax 0.00172%, amr) (gnomAD).

What do computational predictors say about FKRP p.Pro89Ser (c.265C>T)?

AlphaMissense predicts likely pathogenic (score 0.9648) — an in-silico prediction, not a clinical call.

FKRP p.Pro89Ser

Q: What condition is associated with FKRP p.Pro89Ser (c.265C>T)?

FKRP p.Pro89Ser (c.265C>T) is associated with FKRP-related disorder, muscular dystrophy-dystroglycanopathy type B5, autosomal recessive limb-girdle muscular dystrophy type 2I (ClinVar).

c.265C>T · VCV3584042

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9648 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00172%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FKRP-related disorder

Computational evidence

Protein change
AlphaMissense	0.9648	likely pathogenic ✓ concordant with ClinVar
REVEL	0.824	moderately pathogenic-leaning
SaProt	LLR -10.25	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 7.4	GERP 1.4, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,484 bp · p 0.11 · regional, not allelic
Overall
CADD	24.8	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 0.00172% Admixed American · 1/58,116 alleles

Overall 0.000657% 1/152,224 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.Pro89Ser
Coding: c.265C>T
MANE Select: NM_024301
Type: single nucleotide variant
Location: chr19:46755715 (GRCh38)
Gene constraint: LOEUF 1.543 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.08 · 8 PDB

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

Disease context

FKRP-related disorder

Also linked: 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.Pro89Ala Pathogenic/Likely pathogenic ★★ ⚠ same residue
FKRP p.Pro89Leu Pathogenic/Likely pathogenic ★★ ⚠ same residue
FKRP p.Pro89Arg Likely pathogenic ★ ⚠ same residue
FKRP p.Pro89= Likely benign ★★ 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-pro89ser (accessed [today's date]).

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