Is PHKA2 p.Phe321= (c.963C>T) pathogenic?

PHKA2 p.Phe321= (c.963C>T) is classified Benign/Likely benign in PHKA2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-25). Low-frequency (popmax 1.78%, afr); Associated with glycogen storage disease IXa1.

What condition is associated with PHKA2 p.Phe321= (c.963C>T)?

PHKA2 p.Phe321= (c.963C>T) is associated with glycogen storage disease IXa1 (ClinVar).

How common is PHKA2 p.Phe321= (c.963C>T) in the general population?

PHKA2 p.Phe321= (c.963C>T) is low-frequency (popmax 1.78%, afr) (gnomAD).

PHKA2 p.Phe321=

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

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

c.963C>T · rs35010660 · VCV384572

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.78%, afr)

Conditions

glycogen storage disease IXa1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.27	donor loss · deltas
Constraint at this position
Conservation	phyloP 2.1	GERP -2.9, phastCons 1
Overall
CADD	6.849	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.78% African / African-American · 1,018/57,226 alleles

Filtering AF 1.69% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.65%

Overall 0.0917% 1,104/1,203,325 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.78%	56
Remaining individualsnot grpmax-eligible	0.0886%	1,128
Admixed American	0.0785%	1,274
Middle Eastern	0.023%	4,339
Finnishnot grpmax-eligible	0.00215%	46,609
European (non-Finnish)	0.000675%	148,133

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: PHKA2
Protein: p.Phe321=
Coding: c.963C>T
MANE Select: NM_000292
dbSNP: rs35010660
Type: single nucleotide variant
Location: chrX:18938705 (GRCh38)
Structure: AlphaFold pLDDT 81.36

Full PHKA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

glycogen storage disease IXa1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Inheritance: Autosomal recessive, X-linked recessive
Onset: Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

PHKA2 c.1325-2A>G Likely pathogenic ★★ same condition
PHKA2 c.2597+1G>A Pathogenic/Likely pathogenic ★★ same condition
PHKA2 c.537+2T>C Pathogenic/Likely pathogenic ★★ same condition
PHKA2 c.918+1G>A Pathogenic/Likely pathogenic ★★ same condition
PHKA2 p.Arg1111Ter Pathogenic ★★ same condition
PHKA2 p.Arg186Cys Pathogenic/Likely pathogenic ★★ same condition
PHKA2 p.Arg186His Likely pathogenic ★★ same condition
PHKA2 p.Arg295Cys 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/phka2-p-phe321 (accessed [today's date]).

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