Is PHKA2 p.Arg248= (c.742A>C) pathogenic?

PHKA2 p.Arg248= (c.742A>C) is classified Benign/Likely benign in PHKA2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-28). Rare (popmax 0.229%, nfe); Associated with glycogen storage disease IXa1.

What condition is associated with PHKA2 p.Arg248= (c.742A>C)?

PHKA2 p.Arg248= (c.742A>C) is associated with glycogen storage disease IXa1 (ClinVar).

How common is PHKA2 p.Arg248= (c.742A>C) in the general population?

PHKA2 p.Arg248= (c.742A>C) is rare (popmax 0.229%, nfe) (gnomAD).

PHKA2 p.Arg248=

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.742A>C · rs149219369 · VCV198712

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.229%, nfe)

Conditions

glycogen storage disease IXa1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.94 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.6	GERP -0.8, phastCons 0.98
Overall
CADD	9.08	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.229% European (non-Finnish) · 1,967/860,339 alleles

Filtering AF 0.22% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.217%

Overall 0.179% 2,096/1,172,943 alleles · rare exomes 1,949/1,059,730 · genomes 147/113,213 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.229%	437
Remaining individualsnot grpmax-eligible	0.164%	610
Admixed American	0.0675%	1,480
Middle Eastern	0.0466%	2,145
African / African-American	0.0281%	3,558
Finnishnot grpmax-eligible	0.00427%	23,405
South Asian	0.00357%	28,050

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.Arg248=
Coding: c.742A>C
MANE Select: NM_000292
dbSNP: rs149219369
Type: single nucleotide variant
Location: chrX:18941651 (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-arg248 (accessed [today's date]).

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