# NM_000292.3(PHKA2):c.963C>T (p.Phe321=)

https://sugi.bio/variant/phka2-p-phe321

## Summary

**PHKA2 p.Phe321= (c.963C>T)** is classified **Benign/Likely benign** in PHKA2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-25). Low-frequency (popmax 1.78%, afr); Associated with glycogen storage disease IXa1.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs35010660 · 4 submitters · 1 linked condition · low-frequency (popmax 1.78%, afr)

## For patients & families {#patients}

This is a change in the PHKA2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 4 submitters, and is linked to glycogen storage disease IXa1.

*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, X-linked recessive |
| Age of onset (of this condition) | Childhood |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PHKA2 is a diagnostic-grade gene on 8 Genomics England panels |

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

- Hepatomegaly — Very frequent (99-80%)
- Elevated circulating hepatic transaminase concentration — Very frequent (99-80%)
- Abnormal enzyme/coenzyme activity — Very frequent (99-80%)
- Abnormal erythrocyte enzyme activity — Very frequent (99-80%)
- Hepatic fibrosis — Frequent (79-30%)
- Growth delay — Frequent (79-30%)
- Hypoglycemia — Frequent (79-30%)
- Ketosis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018386/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PHKA2](https://sugi.bio/atlas/gene/PHKA2/) |
| Protein change (HGVS p.) | p.Phe321= |
| Coding change (HGVS c.) | c.963C>T |
| MANE Select transcript | [NM_000292](https://www.ncbi.nlm.nih.gov/nuccore/NM_000292) |
| dbSNP | [rs35010660](https://www.ncbi.nlm.nih.gov/snp/rs35010660/) |
| Variant type | single nucleotide variant |
| Location | chrX:18938705-18938705 (GRCh38) |
| ClinVar | [VCV384572](https://www.ncbi.nlm.nih.gov/clinvar/variation/384572/) |

**All HGVS expressions:** `NC_000023.10:g.18956823G>A`, `NC_000023.11:g.18938705G>A`, `NG_016622.1:g.50658C>T`, `NM_000292.3:c.963C>T`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.27) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 2.106, GERP -2.91, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 6.849**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.27**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.27**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **1.78%** (afr) · FAF95 1.69% · FAF99 1.65% · 1,018/57,226 in the highest group · 1,104/1,203,325 alleles overall — low-frequency (popmax 1.78%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 1.78% | 56 |
| Remaining individuals (not grpmax-eligible) | 0.0886% | 1,128 |
| Admixed American | 0.0785% | 1,274 |
| Middle Eastern | 0.023% | 4,339 |
| Finnish (not grpmax-eligible) | 0.00215% | 46,609 |
| European (non-Finnish) | 0.000675% | 148,133 |

*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.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.36, 50% of residues very-high.

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

*Describes the biological roles of PHKA2 (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}

PHKA2 participates in **1 Reactome pathway** (⚕ = disease pathway):

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

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-25.

**Submitter consensus:** conflicting (3 Benign, 1 Likely benign).

**Submission history:** 4 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-25 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-11 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2016-09-07 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

[glycogen storage disease IXa1](https://sugi.bio/atlas/disease/glycogen-storage-disease-ixa1/).

**Reported phenotype names (ClinVar):** Glycogen storage disease IXa1, not specified, not provided, LIVER GLYCOGENOSIS, X-LINKED, TYPE I, GLYCOGEN STORAGE DISEASE VIII, GSD VIII, Glycogen storage disease 8, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related PHKA2 variant pages (same residue, condition, or type): [PHKA2 c.1325-2A>G](/variant/phka2-c-1325-minus-2a-g), [PHKA2 c.2597+1G>A](/variant/phka2-c-2597-plus-1g-a), [PHKA2 c.537+2T>C](/variant/phka2-c-537-plus-2t-c), [PHKA2 c.918+1G>A](/variant/phka2-c-918-plus-1g-a), [PHKA2 p.Arg1111Ter](/variant/phka2-p-arg1111ter), [PHKA2 p.Arg186Cys](/variant/phka2-p-arg186cys), [PHKA2 p.Arg186His](/variant/phka2-p-arg186his), [PHKA2 p.Arg295Cys](/variant/phka2-p-arg295cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 384572). 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.*