Is PHKB p.Leu149Phe (c.445C>T) pathogenic?

PHKB p.Leu149Phe (c.445C>T) is classified Uncertain significance in PHKB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-14). AlphaMissense: likely pathogenic (0.6798); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with PHKB p.Leu149Phe (c.445C>T)?

PHKB p.Leu149Phe (c.445C>T) is associated with Inborn genetic diseases, glycogen storage disease IXb (ClinVar).

How common is PHKB p.Leu149Phe (c.445C>T) in the general population?

PHKB p.Leu149Phe (c.445C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about PHKB p.Leu149Phe (c.445C>T)?

AlphaMissense predicts likely pathogenic (score 0.6798) — an in-silico prediction, not a clinical call.

PHKB p.Leu149Phe

c.445C>T · rs370363309 · VCV884838

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6798 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6798	likely pathogenic
REVEL	0.846	moderately pathogenic-leaning
SaProt	LLR -8.88	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 238 kb · p 0.5 · regional, not allelic
Overall
CADD	27.9	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.0053% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0049%

Overall 0.00539% 87/1,613,256 alleles · ultra-rare exomes 79/1,461,106 · genomes 8/152,150 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.00653%	15,316
Remaining individualsnot grpmax-eligible	0.0064%	15,614
South Asian	0.00549%	18,214

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.Leu149Phe
Coding: c.445C>T
MANE Select: NM_000293
dbSNP: rs370363309
Type: single nucleotide variant
Location: chr16:47511704 (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 149: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: glycogen storage disease IXb

Similar variants

PHKB p.Leu149= 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-leu149phe (accessed [today's date]).

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