Is PHKB p.Ala741Asp (c.2222C>A) pathogenic?

PHKB p.Ala741Asp (c.2222C>A) is classified Uncertain significance in PHKB (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-05). AlphaMissense: likely pathogenic (0.8754); No allele count reported in gnomAD v4.1 (AN 1,613,262); Associated with glycogen storage disease IXb.

What condition is associated with PHKB p.Ala741Asp (c.2222C>A)?

PHKB p.Ala741Asp (c.2222C>A) is associated with glycogen storage disease IXb (ClinVar).

How common is PHKB p.Ala741Asp (c.2222C>A) in the general population?

PHKB p.Ala741Asp (c.2222C>A) is no allele count reported in gnomAD v4.1 (AN 1,613,262) (gnomAD).

What do computational predictors say about PHKB p.Ala741Asp (c.2222C>A)?

AlphaMissense predicts likely pathogenic (score 0.8754) — an in-silico prediction, not a clinical call.

PHKB p.Ala741Asp

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

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

c.2222C>A · rs2506609993 · VCV2434700

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8754 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,613,262)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease IXb

Computational evidence

Protein change
AlphaMissense	0.8754	likely pathogenic
REVEL	0.778	moderately pathogenic-leaning
SaProt	LLR -10.92	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.8	GERP -1.5, phastCons 0.3
Regional constraint	o/e 0.98	unconstrained · MANE · 238 kb · p 0.5 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,613,262). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PHKB
Protein: p.Ala741Asp
Coding: c.2222C>A
MANE Select: NM_000293
dbSNP: rs2506609993
Type: single nucleotide variant
Location: chr16:47661744 (GRCh38)
Gene constraint: LOEUF 0.792 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.06 · 6 PDB
Residue 741: an α-helix

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

Disease context

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

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

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

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PHKB c.2896-1G>T Pathogenic ★★ same condition
PHKB c.306-2A>G Pathogenic/Likely pathogenic ★★ same condition
PHKB p.Arg103Ter Pathogenic/Likely pathogenic ★★ same condition
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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/phkb-p-ala741asp (accessed [today's date]).

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