PHKG2

Chr 16

phosphorylase kinase catalytic subunit gamma 2

Also known as: GSD9C

NCBI Gene: 5261 ENSG00000156873 UniProt: P15735

The phosphorylase kinase gamma regulatory subunit catalyzes the phosphorylation and activation of glycogen phosphorylase, which is essential for glycogen breakdown in the liver. Biallelic mutations cause glycogen storage disease type IXc, characterized by hepatomegaly and growth retardation typically presenting in infancy or early childhood with autosomal recessive inheritance. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.657), primarily affecting hepatic glycogen metabolism.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

Phosphorylase kinase is a polymer of 16 subunits, four each of alpha, beta, gamma and delta. The alpha subunit includes the skeletal muscle and hepatic isoforms, encoded by two different genes. The beta subunit is the same in both the muscle and hepatic isoforms, and encoded by one gene. The gamma subunit also includes the skeletal muscle and hepatic isoforms, and the hepatic isoform is encoded by this gene. The delta subunit is a calmodulin and can be encoded by three different genes. The gamma subunits contain the active site of the enzyme, whereas the alpha and beta subunits have regulatory functions controlled by phosphorylation. The delta subunit mediates the dependence of the enzyme on calcium concentration. Mutations in this gene cause glycogen storage disease type 9C, also known as autosomal liver glycogenosis. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene.[provided by RefSeq, Feb 2010]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.66

Clinical Summary— PHKG2

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Gene-Disease Validity (ClinGen)

glycogen storage disease IXc · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

56 unique Pathogenic / Likely Pathogenic· 160 VUS of 511 total submissions

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GeneReview available — PHKG2

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.66LOEUF

pLI 0.004

Z-score 2.76

OE 0.36 (0.21–0.66)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.45Z-score

OE missense 0.92 (0.82–1.03)

228 obs / 247.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.36 (0.21–0.66)

0≤0.351.4

Missense OE?0.92 (0.82–1.03)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 8 / 22.0Missense obs/exp: 228 / 247.9Syn Z: -1.13

This gene — mechanism propensity

0.7132th %ile

GOF

0.82top 10%

LOF

0.2678th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

511 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic38

Likely Pathogenic18

VUS160

Likely Benign225

Benign18

Conflicting23

Pathogenic

Likely Pathogenic

160

VUS

225

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	30	6	2	0	38
Likely Pathogenic	9	8	1	0	18
VUS	3	142	14	1	160
Likely Benign	0	9	84	132	225
Benign	0	1	16	1	18
Conflicting	—				23
Total	42	166	117	134	482

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

10 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap PHKG2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →