Is PHKB p.Pro525His (c.1574C>A) pathogenic?

PHKB p.Pro525His (c.1574C>A) is classified Conflicting classifications of pathogenicity in PHKB (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-14). AlphaMissense: likely pathogenic (0.9842); Rare (popmax 0.488%, afr); Associated with glycogen storage disease IXb.

What condition is associated with PHKB p.Pro525His (c.1574C>A)?

PHKB p.Pro525His (c.1574C>A) is associated with glycogen storage disease IXb (ClinVar).

How common is PHKB p.Pro525His (c.1574C>A) in the general population?

PHKB p.Pro525His (c.1574C>A) is rare (popmax 0.488%, afr) (gnomAD).

What do computational predictors say about PHKB p.Pro525His (c.1574C>A)?

AlphaMissense predicts likely pathogenic (score 0.9842) — an in-silico prediction, not a clinical call.

PHKB p.Pro525His

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.1574C>A · rs79509460 · VCV731875

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9842 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.488%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease IXb

Computational evidence

Protein change
AlphaMissense	0.9842	likely pathogenic · top 5% in PHKB
REVEL	0.811	moderately pathogenic-leaning
SaProt	LLR -9.32	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 238 kb · p 0.5 · regional, not allelic
Overall
CADD	26.7	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 0.488% African / African-American · 365/74,852 alleles

Filtering AF 0.446% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.43%

Overall 0.0271% 435/1,605,514 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.488%	205
Remaining individualsnot grpmax-eligible	0.0546%	1,830
Admixed American	0.05%	2,000
Middle Eastern	0.0165%	6,050
South Asian	0.0011%	90,904
European (non-Finnish)	0.000341%	293,044

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.Pro525His
Coding: c.1574C>A
MANE Select: NM_000293
dbSNP: rs79509460
Type: single nucleotide variant
Location: chr16:47641658 (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 525: a β-strand

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

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PHKB c.2427+965A>C Pathogenic/Likely pathogenic ★★ same condition
PHKB c.2896-1G>T Pathogenic ★★ same condition
PHKB c.306-2A>G Pathogenic/Likely pathogenic ★★ same condition
PHKB p.Arg103Ter Pathogenic/Likely pathogenic ★★ same condition
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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-pro525his (accessed [today's date]).

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