Is PHKA2 p.Arg1069His (c.3206G>A) pathogenic?

PHKA2 p.Arg1069His (c.3206G>A) is classified Uncertain significance in PHKA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-21). AlphaMissense: likely pathogenic (0.8328); Very rare (popmax 0.00528%, sas); Associated with glycogen storage disease IXa1.

What condition is associated with PHKA2 p.Arg1069His (c.3206G>A)?

PHKA2 p.Arg1069His (c.3206G>A) is associated with glycogen storage disease IXa1 (ClinVar).

How common is PHKA2 p.Arg1069His (c.3206G>A) in the general population?

PHKA2 p.Arg1069His (c.3206G>A) is very rare (popmax 0.00528%, sas) (gnomAD).

What do computational predictors say about PHKA2 p.Arg1069His (c.3206G>A)?

AlphaMissense predicts likely pathogenic (score 0.8328) — an in-silico prediction, not a clinical call.

PHKA2 p.Arg1069His

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.3206G>A · VCV4745516

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8328 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00528%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease IXa1

Computational evidence

Protein change
AlphaMissense	0.8328	likely pathogenic
REVEL	0.902	moderately pathogenic-leaning
SaProt	LLR -8.07	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 45 kb · p 0.0065 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00528% South Asian · 3/56,802 alleles

Filtering AF 0.0014% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000689%

Overall 0.00132% 16/1,208,894 alleles · very rare exomes 15/1,096,924 · genomes 1/111,970 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00528%	18,934
Remaining individualsnot grpmax-eligible	0.00421%	23,774
African / African-American	0.00349%	28,626
East Asian	0.00296%	33,742
Finnishnot grpmax-eligible	0.00218%	45,794
European (non-Finnish)	0.000782%	127,837

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.Arg1069His
Coding: c.3206G>A
MANE Select: NM_000292
Type: single nucleotide variant
Location: chrX:18897239 (GRCh38)
Structure: AlphaFold pLDDT 81.36
Residue 1069: the 'calmodulin-binding' region

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 p.Arg1069Cys Uncertain significance ★ ⚠ same residue
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

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-arg1069his (accessed [today's date]).

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