Is PHKB p.Leu440Pro (c.1319T>C) pathogenic?

PHKB p.Leu440Pro (c.1319T>C) is classified Uncertain significance in PHKB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-12). AlphaMissense: ambiguous (0.4685); Ultra-rare (popmax 0.0118%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PHKB p.Leu440Pro (c.1319T>C)?

PHKB p.Leu440Pro (c.1319T>C) is associated with Inborn genetic diseases, glycogen storage disease IXb (ClinVar).

How common is PHKB p.Leu440Pro (c.1319T>C) in the general population?

PHKB p.Leu440Pro (c.1319T>C) is ultra-rare (popmax 0.0118%, nfe) (gnomAD).

What do computational predictors say about PHKB p.Leu440Pro (c.1319T>C)?

AlphaMissense predicts ambiguous (score 0.4685) — an in-silico prediction, not a clinical call.

PHKB p.Leu440Pro

c.1319T>C · rs140509147 · VCV2060577

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4685 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0118%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4685	ambiguous
REVEL	0.649	pathogenic-leaning
SaProt	LLR -2.96	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 238 kb · p 0.5 · regional, not allelic
Overall
CADD	26.8	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 0.0118% European (non-Finnish) · 139/1,179,876 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00956%

Overall 0.00898% 145/1,613,854 alleles · ultra-rare exomes 137/1,461,670 · genomes 8/152,184 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0118%	8,488
Remaining individualsnot grpmax-eligible	0.0064%	15,619
African / African-American	0.00267%	37,463

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.Leu440Pro
Coding: c.1319T>C
MANE Select: NM_000293
dbSNP: rs140509147
Type: single nucleotide variant
Location: chr16:47596487 (GRCh38)
Gene constraint: LOEUF 0.792 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.06 · 6 PDB

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 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-leu440pro (accessed [today's date]).

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