PHKA1

Chr XXLR

phosphorylase kinase regulatory subunit alpha 1

Also known as: PHKA

NCBI Gene: 5255 ENSG00000067177 UniProt: P46020 OMIM: 311870

The PHKA1 gene encodes the alpha subunit of phosphorylase kinase, which catalyzes phosphorylation of substrates including troponin I and regulates glycogen breakdown in skeletal muscle. Mutations cause X-linked recessive muscle glycogenosis (glycogen storage disease type 9D), presenting as muscle weakness and exercise intolerance. This gene is highly constrained against loss-of-function variants (LOEUF 0.547), indicating that such mutations are likely pathogenic.

GeneReviews OMIM 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, and the skeletal muscle isoform is encoded by this gene. 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, which are encoded by two different genes. 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 9D, also known as X-linked muscle glycogenosis. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene. A pseudogene has been found on chromosome 1.[provided by RefSeq, Feb 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismXLRLOEUF 0.551 OMIM phenotype

Clinical Summary— PHKA1

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Gene-Disease Validity (ClinGen)

glycogen storage disease IXd · XLDefinitive

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

50 unique Pathogenic / Likely Pathogenic· 367 VUS of 930 total submissions

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GeneReview available — PHKA1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.55LOEUF

pLI 0.000

Z-score 4.33

OE 0.38 (0.27–0.55)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.88Z-score

OE missense 0.76 (0.69–0.83)

363 obs / 478.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.38 (0.27–0.55)

0≤0.351.4

Missense OE?0.76 (0.69–0.83)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 22 / 57.4Missense obs/exp: 363 / 478.8Syn Z: -0.55

This gene — mechanism propensity

0.6455th %ile

GOF

0.7125th %ile

LOF

0.3358th %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

930 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25

Likely Pathogenic25

VUS367

Likely Benign238

Benign49

Conflicting32

Pathogenic

Likely Pathogenic

367

VUS

238

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	22	0	3	0	25
Likely Pathogenic	24	0	1	0	25
VUS	5	320	40	2	367
Likely Benign	0	8	117	113	238
Benign	0	2	37	10	49
Conflicting	—				32
Total	51	330	198	125	736

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

View in ClinVar →

56 pathogenic / likely-pathogenic (of 70) ClinVar copy-number / structural variants overlap PHKA1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →