Is PHKA2 p.Ala146Ser (c.436G>T) pathogenic?

PHKA2 p.Ala146Ser (c.436G>T) is classified Likely pathogenic in PHKA2 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-08-07). AlphaMissense: likely benign (0.1631); Very rare (popmax 0.000558%, nfe); Associated with glycogen storage disease IXa1.

What condition is associated with PHKA2 p.Ala146Ser (c.436G>T)?

PHKA2 p.Ala146Ser (c.436G>T) is associated with glycogen storage disease IXa1 (ClinVar).

How common is PHKA2 p.Ala146Ser (c.436G>T) in the general population?

PHKA2 p.Ala146Ser (c.436G>T) is very rare (popmax 0.000558%, nfe) (gnomAD).

What do computational predictors say about PHKA2 p.Ala146Ser (c.436G>T)?

AlphaMissense predicts likely benign (score 0.1631) — an in-silico prediction, not a clinical call.

PHKA2 p.Ala146Ser

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.436G>T · VCV4056432

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1631 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000558%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease IXa1

Computational evidence

Protein change
AlphaMissense	0.1631	likely benign ⚠ discordant with ClinVar
REVEL	0.801	moderately pathogenic-leaning
SaProt	LLR -9.82	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.87, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 45 kb · p 5e-08 · regional, not allelic
Overall
CADD	24.5	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 0.000558% European (non-Finnish) · 5/895,451 alleles

Filtering AF 0.000164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000119%

Overall 0.000455% 5/1,098,063 alleles · very rare

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.Ala146Ser
Coding: c.436G>T
MANE Select: NM_000292
Type: single nucleotide variant
Location: chrX:18951122 (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-ala146ser (accessed [today's date]).

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