Is PHKB p.Ser27Leu (c.80C>T) pathogenic?

PHKB p.Ser27Leu (c.80C>T) is classified Uncertain significance in PHKB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-06). AlphaMissense: likely benign (0.2191); Ultra-rare (popmax 0.0117%, amr); Associated with glycogen storage disease IXb.

What condition is associated with PHKB p.Ser27Leu (c.80C>T)?

PHKB p.Ser27Leu (c.80C>T) is associated with glycogen storage disease IXb (ClinVar).

How common is PHKB p.Ser27Leu (c.80C>T) in the general population?

PHKB p.Ser27Leu (c.80C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about PHKB p.Ser27Leu (c.80C>T)?

AlphaMissense predicts likely benign (score 0.2191) — an in-silico prediction, not a clinical call.

PHKB p.Ser27Leu

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.80C>T · rs769640225 · VCV1978388

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2191 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease IXb

Computational evidence

Protein change
AlphaMissense	0.2191	likely benign
REVEL	0.716	pathogenic-leaning
SaProt	LLR -7.70	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 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 238 kb · p 0.5 · regional, not allelic
Overall
CADD	24.8	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 0.0117% Admixed American · 7/59,926 alleles

Filtering AF 0.00544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000488% 7/1,434,640 alleles · ultra-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: PHKB
Protein: p.Ser27Leu
Coding: c.80C>T
MANE Select: NM_000293
dbSNP: rs769640225
Type: single nucleotide variant
Location: chr16:47497402 (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 27: the 'calmodulin-binding' region; a modified residue (phosphoserine)

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

PHKB p.Ser27Ter Pathogenic ★ same residue
PHKB p.Ser27= Likely benign ★ same residue
PHKB c.1127-2A>G Pathogenic/Likely pathogenic ★★ same condition
PHKB c.1364-2A>G Pathogenic ★★ same condition
PHKB c.1972-2A>G Pathogenic/Likely pathogenic ★★ same condition
PHKB c.2427+965A>C Pathogenic/Likely pathogenic ★★ same condition
PHKB c.2896-1G>T Pathogenic ★★ same condition
PHKB c.306-2A>G 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/phkb-p-ser27leu (accessed [today's date]).

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