# NM_000293.3(PHKB):c.574A>G (p.Ile192Val)

https://sugi.bio/variant/phkb-p-ile192val

## Summary

**PHKB p.Ile192Val (c.574A>G)** is classified **Conflicting classifications of pathogenicity** in PHKB (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1301); Rare (popmax 0.559%, mid); Associated with glycogen storage disease IXb.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs117218785 · 9 submitters · 1 linked condition · AlphaMissense likely benign · rare (popmax 0.559%, mid)

## For patients & families {#patients}

This is a change in the PHKB gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 9 submitters, and is linked to glycogen storage disease IXb.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PHKB is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Glycogen storage disease due to liver and muscle phosphorylase kinase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypertriglyceridemia — Very frequent (99-80%)
- Hepatomegaly — Very frequent (99-80%)
- Postnatal growth retardation — Very frequent (99-80%)
- Abnormal enzyme/coenzyme activity — Very frequent (99-80%)
- Hepatic fibrosis — Frequent (79-30%)
- Elevated circulating hepatic transaminase concentration — Frequent (79-30%)
- Hypercholesterolemia — Frequent (79-30%)
- Fasting hypoglycemia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016711/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PHKB](https://sugi.bio/atlas/gene/PHKB/) |
| Protein change (HGVS p.) | p.Ile192Val |
| Coding change (HGVS c.) | c.574A>G |
| MANE Select transcript | [NM_000293](https://www.ncbi.nlm.nih.gov/nuccore/NM_000293) |
| dbSNP | [rs117218785](https://www.ncbi.nlm.nih.gov/snp/rs117218785/) |
| Variant type | single nucleotide variant |
| Location | chr16:47515581-47515581 (GRCh38) |
| ClinVar | [VCV516456](https://www.ncbi.nlm.nih.gov/clinvar/variation/516456/) |

**All HGVS expressions:** `NC_000016.10:g.47515581A>G`, `NC_000016.9:g.47549492A>G`, `NG_016598.1:g.59283A>G`, `NM_000293.3:c.574A>G`, `NM_001031835.3:c.553A>G`, `NM_001363837.1:c.574A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1301)
- REVEL 0.625 (indeterminate)
- SaProt LLR -8.668 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 6.82, GERP 1.93, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.8**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.98** across the covering region of the MANE Select transcript (47,461,351–47,699,363), spanning 238,012 bp. Chi-square p 0.5. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.559%** (mid) · FAF95 0.407% · FAF99 0.355% · 32/5,720 in the highest group · 2,082/1,437,504 alleles overall — rare (popmax 0.559%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.559% | 179 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.344% | 291 |
| European (non-Finnish) | 0.165% | 605 |
| Finnish (not grpmax-eligible) | 0.151% | 661 |
| Remaining individuals (not grpmax-eligible) | 0.124% | 809 |
| Admixed American | 0.0903% | 1,107 |
| South Asian | 0.0354% | 2,823 |
| African / African-American | 0.0237% | 4,219 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**PHKB** population constraint: LOEUF 0.792, pLI 1.2179e-07, missense-Z 0.87257; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **glycogen storage disease IXb** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 87.06, 64% of residues very-high.

**6 experimental structure(s)** (PDB): [8JFK](https://www.rcsb.org/structure/8JFK), [8JFL](https://www.rcsb.org/structure/8JFL), [8XYA](https://www.rcsb.org/structure/8XYA), [8Z5P](https://www.rcsb.org/structure/8Z5P), [8Z5Q](https://www.rcsb.org/structure/8Z5Q), [8Z5T](https://www.rcsb.org/structure/8Z5T).

## What this gene does {#gene-function}

*Describes the biological roles of PHKB (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

PHKB participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glycogen breakdown (glycogenolysis)](https://reactome.org/content/detail/R-HSA-70221) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** glycogen catabolic process.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (5 Likely benign, 2 Uncertain significance, 1 Likely Benign).

**Submission history:** 24 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-22 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-02-26 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely Benign | criteria provided, single submitter | clinical testing | 2024-06-25 |
| Genomic Research Center, Shahid Beheshti University of Medical Sciences | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-03-05 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |

## Associated conditions {#conditions}

[glycogen storage disease IXb](https://sugi.bio/atlas/disease/glycogen-storage-disease-ixb/).

**Reported phenotype names (ClinVar):** Glycogen storage disease IXb, not specified, not provided, PHKB-related disorder, Clear cell carcinoma of kidney, Colon adenocarcinoma, Gastric cancer, Ovarian serous cystadenocarcinoma, Melanoma, Malignant tumor of esophagus.

## Similar variants {#similar}

Related PHKB variant pages (same residue, condition, or type): [PHKB c.1127-2A>G](/variant/phkb-c-1127-minus-2a-g), [PHKB c.1364-2A>G](/variant/phkb-c-1364-minus-2a-g), [PHKB c.1972-2A>G](/variant/phkb-c-1972-minus-2a-g), [PHKB c.2427+965A>C](/variant/phkb-c-2427-plus-965a-c), [PHKB c.2896-1G>T](/variant/phkb-c-2896-minus-1g-t), [PHKB c.306-2A>G](/variant/phkb-c-306-minus-2a-g), [PHKB p.Arg103Ter](/variant/phkb-p-arg103ter), [PHKB p.Arg429Ter](/variant/phkb-p-arg429ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 516456). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*