Is PHKB p.Arg768fs (c.2304_2305del) pathogenic?

PHKB p.Arg768fs (c.23042305del) is classified Pathogenic/Likely pathogenic in PHKB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-20). Very rare (popmax 8.48e-05%, nfe); Associated with glycogen storage disease IXb.

What condition is associated with PHKB p.Arg768fs (c.2304_2305del)?

PHKB p.Arg768fs (c.2304_2305del) is associated with glycogen storage disease IXb (ClinVar).

How common is PHKB p.Arg768fs (c.2304_2305del) in the general population?

PHKB p.Arg768fs (c.2304_2305del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

PHKB p.Arg768fs

Q: How is Glycogen storage disease due to liver and muscle phosphorylase kinase deficiency inherited?

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

c.2304_2305del · VCV3580747

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

glycogen storage disease IXb

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 24 of 31
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.5	GERP -2.4, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,178,884 alleles

Overall 0.000186% 3/1,612,664 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,795
European (non-Finnish)grpmax	8.48e-05%	1,178,884

Ashkenazi Jewish 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: PHKB
Protein: p.Arg768fs
Coding: c.2304_2305del
MANE Select: NM_000293
Type: Microsatellite
Location: chr16:47663697 (GRCh38)
Gene constraint: LOEUF 0.792 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.06 · 6 PDB
Residue 768: the 'calmodulin-binding' region; an α-helix

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

Disease context

glycogen storage disease IXb — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glycogen storage disease due to liver and muscle phosphorylase kinase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

PHKB p.Glu820del Benign ★★ same condition
PHKB p.Gly124fs Pathogenic ★ same condition
PHKB p.Ser289_His290insTer Pathogenic ★ same condition
PHKB c.1126+1GTAA[3] Likely benign ★ same condition
PHKB c.1126+30_1126+52del Likely benign ★ same condition
PHKB c.1364-11_1364-9del Likely benign ★ same condition
PHKB c.1881-13_1881-10del Likely benign ★ same condition
PHKB c.2336+22_2336+24del Likely benign ★ 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/phkb-p-arg768fs (accessed [today's date]).

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