Is PHKB p.Arg1041Trp (c.3121C>T) pathogenic?

PHKB p.Arg1041Trp (c.3121C>T) is classified Benign/Likely benign in PHKB (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-07-01). AlphaMissense: likely benign (0.1026); Low-frequency (popmax 1.33%, nfe); Associated with glycogen storage disease IXb.

What condition is associated with PHKB p.Arg1041Trp (c.3121C>T)?

PHKB p.Arg1041Trp (c.3121C>T) is associated with glycogen storage disease IXb (ClinVar).

How common is PHKB p.Arg1041Trp (c.3121C>T) in the general population?

PHKB p.Arg1041Trp (c.3121C>T) is low-frequency (popmax 1.33%, nfe) (gnomAD).

What do computational predictors say about PHKB p.Arg1041Trp (c.3121C>T)?

AlphaMissense predicts likely benign (score 0.1026) — an in-silico prediction, not a clinical call.

PHKB p.Arg1041Trp

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.3121C>T · rs12918964 · VCV319360

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1026 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.33%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease IXb

Computational evidence

Protein change
AlphaMissense	0.1026	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -9.35	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 1.6, phastCons 0.97
Regional constraint	o/e 0.98	unconstrained · MANE · 238 kb · p 0.5 · regional, not allelic
Overall
CADD	23.6	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 1.33% European (non-Finnish) · 14,781/1,112,574 alleles

Filtering AF 1.31% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.3%

Overall 1.06% 16,114/1,518,908 alleles · low-frequency

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.79%	56
European (non-Finnish)grpmax	1.33%	75
Remaining individualsnot grpmax-eligible	1.15%	87
Finnishnot grpmax-eligible	0.467%	214
Admixed American	0.315%	317
African / African-American	0.2%	499
Middle Eastern	0.129%	773
South Asian	0.0508%	1,967
Ashkenazi Jewishnot grpmax-eligible	0.0179%	5,576
East Asian	0.00728%	13,728

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1041Trp
Coding: c.3121C>T
MANE Select: NM_000293
dbSNP: rs12918964
Type: single nucleotide variant
Location: chr16:47698565 (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 1041: 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.Arg1041Gln Uncertain significance ★★ ⚠ same residue
PHKB p.Arg1041= Likely benign ★ same residue
PHKB p.Arg1041Pro Uncertain significance ★ ⚠ 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

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-arg1041trp (accessed [today's date]).

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