Is PHKB p.Arg436His (c.1307G>A) pathogenic?

PHKB p.Arg436His (c.1307G>A) is classified Uncertain significance in PHKB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-20). AlphaMissense: likely benign (0.0826); Ultra-rare (popmax 0.0223%, eas); Associated with Inborn genetic diseases.

What condition is associated with PHKB p.Arg436His (c.1307G>A)?

PHKB p.Arg436His (c.1307G>A) is associated with Inborn genetic diseases, glycogen storage disease IXb (ClinVar).

How common is PHKB p.Arg436His (c.1307G>A) in the general population?

PHKB p.Arg436His (c.1307G>A) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about PHKB p.Arg436His (c.1307G>A)?

AlphaMissense predicts likely benign (score 0.0826) — an in-silico prediction, not a clinical call.

PHKB p.Arg436His

c.1307G>A · rs143602657 · VCV1494883

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0826 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0826	likely benign
REVEL	0.338	indeterminate
SaProt	LLR -6.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 238 kb · p 0.5 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0223% East Asian · 10/44,860 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00917%

Overall 0.00595% 96/1,613,820 alleles · ultra-rare exomes 87/1,461,564 · genomes 9/152,256 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,486
Finnishnot grpmax-eligible	0.0109%	9,145
South Asian	0.00988%	10,120
Admixed American	0.00833%	12,004
European (non-Finnish)	0.00509%	19,663
Remaining individualsnot grpmax-eligible	0.0048%	20,834
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
African / African-American	0.00133%	75,018

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.Arg436His
Coding: c.1307G>A
MANE Select: NM_000293
dbSNP: rs143602657
Type: single nucleotide variant
Location: chr16:47596475 (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 436: a β-strand

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.Arg436Cys 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
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-arg436his (accessed [today's date]).

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