Is PHKB p.Ala118Pro (c.352G>C) pathogenic?

PHKB p.Ala118Pro (c.352G>C) is classified Conflicting classifications of pathogenicity in PHKB (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-08). AlphaMissense: likely pathogenic (0.9895); Ultra-rare (popmax 0.0217%, amr); Associated with PHKB-related disorder.

What condition is associated with PHKB p.Ala118Pro (c.352G>C)?

PHKB p.Ala118Pro (c.352G>C) is associated with PHKB-related disorder, glycogen storage disease IXb (ClinVar).

How common is PHKB p.Ala118Pro (c.352G>C) in the general population?

PHKB p.Ala118Pro (c.352G>C) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about PHKB p.Ala118Pro (c.352G>C)?

AlphaMissense predicts likely pathogenic (score 0.9895) — an in-silico prediction, not a clinical call.

PHKB p.Ala118Pro

c.352G>C · rs121918022 · VCV13622

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9895 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PHKB-related disorder

Computational evidence

Protein change
AlphaMissense	0.9895	likely pathogenic · top 4% in PHKB
REVEL	0.909	moderately pathogenic-leaning
SaProt	LLR -12.39	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 9.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 238 kb · p 0.5 · regional, not allelic
Overall
CADD	28.8	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 0.0217% Admixed American · 13/60,010 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00136% 22/1,613,658 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,616
Remaining individualsnot grpmax-eligible	0.0016%	62,468
European (non-Finnish)	0.000678%	147,459

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.Ala118Pro
Coding: c.352G>C
MANE Select: NM_000293
dbSNP: rs121918022
Type: single nucleotide variant
Location: chr16:47503037 (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 118: a UniProt-annotated variant site (in gsd9b); an α-helix

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

Disease context

PHKB-related disorder

Also linked: glycogen storage disease IXb

Similar variants

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
PHKB p.Arg429Ter 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-ala118pro (accessed [today's date]).

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