Is PHKB p.Pro993Thr (c.2977C>A) pathogenic?

PHKB p.Pro993Thr (c.2977C>A) is classified Uncertain significance in PHKB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-12). AlphaMissense: likely pathogenic (0.6975); Very rare (popmax 8.6e-05%, nfe); Associated with glycogen storage disease IXb.

What condition is associated with PHKB p.Pro993Thr (c.2977C>A)?

PHKB p.Pro993Thr (c.2977C>A) is associated with glycogen storage disease IXb (ClinVar).

How common is PHKB p.Pro993Thr (c.2977C>A) in the general population?

PHKB p.Pro993Thr (c.2977C>A) is very rare (popmax 8.6e-05%, nfe) (gnomAD).

What do computational predictors say about PHKB p.Pro993Thr (c.2977C>A)?

AlphaMissense predicts likely pathogenic (score 0.6975) — an in-silico prediction, not a clinical call.

PHKB p.Pro993Thr

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.2977C>A · rs2506732071 · VCV2023921

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6975 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.6e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease IXb

Computational evidence

Protein change
AlphaMissense	0.6975	likely pathogenic
REVEL	0.78	moderately pathogenic-leaning
SaProt	LLR -11.41	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 238 kb · p 0.5 · regional, not allelic
Overall
CADD	24.9	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

Grpmax group 8.6e-05% European (non-Finnish) · 1/1,163,322 alleles

Overall 6.27e-05% 1/1,595,830 alleles · very rare exomes 1/1,443,618 · genomes 0/152,212 · joint denominator

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.Pro993Thr
Coding: c.2977C>A
MANE Select: NM_000293
dbSNP: rs2506732071
Type: single nucleotide variant
Location: chr16:47696462 (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 993: 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

PHKB p.Pro993= 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
PHKB p.Arg103Ter 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-pro993thr (accessed [today's date]).

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