Is PHKA2 p.Phe748= (c.2244T>C) pathogenic?

PHKA2 p.Phe748= (c.2244T>C) is classified Likely benign in PHKA2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-10-07). Ultra-rare (popmax 0.0175%, afr); Associated with glycogen storage disease IXa1.

What condition is associated with PHKA2 p.Phe748= (c.2244T>C)?

PHKA2 p.Phe748= (c.2244T>C) is associated with glycogen storage disease IXa1 (ClinVar).

How common is PHKA2 p.Phe748= (c.2244T>C) in the general population?

PHKA2 p.Phe748= (c.2244T>C) is ultra-rare (popmax 0.0175%, afr) (gnomAD).

PHKA2 p.Phe748=

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.2244T>C · rs143626269 · VCV3056479

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, afr)

Conditions

glycogen storage disease IXa1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -2.1, phastCons 1
Overall
CADD	7.387	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0175% African / African-American · 10/57,091 alleles

Filtering AF 0.00942% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.00091% 11/1,208,318 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0175%	5,709
Admixed American	0.00219%	45,696

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.Phe748=
Coding: c.2244T>C
MANE Select: NM_000292
dbSNP: rs143626269
Type: single nucleotide variant
Location: chrX:18908917 (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-phe748 (accessed [today's date]).

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