# NM_002637.4(PHKA1):c.543C>T (p.Phe181=)

https://sugi.bio/variant/phka1-p-phe181

## Summary

**PHKA1 p.Phe181= (c.543C>T)** is classified **Likely benign** in PHKA1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-08-25). Ultra-rare (popmax 0.0141%, afr); Associated with glycogen storage disease IXd.

**At a glance:** Likely benign · review: Single submitter · rsID rs781909169 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0141%, afr)

## For patients & families {#patients}

This is a change in the PHKA1 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to glycogen storage disease IXd.

*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) | Adolescent, Adult |
| Diagnostic panels | PHKA1 is a diagnostic-grade gene on 11 Genomics England panels |

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

- Progressive muscle weakness — Very frequent (99-80%)
- Elevated circulating creatine kinase concentration — Frequent (79-30%)
- Myalgia — Frequent (79-30%)
- EMG: myopathic abnormalities — Frequent (79-30%)
- Exercise intolerance — Frequent (79-30%)
- Increased muscle glycogen content — Frequent (79-30%)
- Fatigue — Frequent (79-30%)
- Reduced muscle phosphorylase kinase activity — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003858/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PHKA1](https://sugi.bio/atlas/gene/PHKA1/) |
| Protein change (HGVS p.) | p.Phe181= |
| Coding change (HGVS c.) | c.543C>T |
| MANE Select transcript | [NM_002637](https://www.ncbi.nlm.nih.gov/nuccore/NM_002637) |
| dbSNP | [rs781909169](https://www.ncbi.nlm.nih.gov/snp/rs781909169/) |
| Variant type | single nucleotide variant |
| Location | chrX:72676145-72676145 (GRCh38) |
| ClinVar | [VCV2039042](https://www.ncbi.nlm.nih.gov/clinvar/variation/2039042/) |

**All HGVS expressions:** `NC_000023.10:g.71895995G>A`, `NC_000023.11:g.72676145G>A`, `NG_016599.2:g.43037C>T`, `NM_001122670.2:c.543C>T`, `NM_001172436.2:c.543C>T`, `NM_002637.3:c.543C>T`, `NM_002637.4:c.543C>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 (below), not from a missing predictor score.
- Conservation: phyloP -4.726, GERP -3.64 — fast-evolving / accelerated position
- CADD: **PHRED 0.101**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.27 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0141%** (afr) · FAF95 0.00696% · FAF99 0.00508% · 8/56,541 in the highest group · 53/1,198,583 alleles overall — ultra-rare (popmax 0.0141%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0141% | 7,068 |
| Admixed American | 0.011% | 9,110 |
| Remaining individuals (not grpmax-eligible) | 0.00635% | 15,758 |
| European (non-Finnish) | 0.00406% | 24,609 |
| South Asian | 0.00178% | 56,318 |

*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}


Curated gene–disease validity (ClinGen):

- **glycogen storage disease IXd** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.84, 54% of residues very-high.

**10 experimental structure(s)** (PDB): [8JFK](https://www.rcsb.org/structure/8JFK), [8JFL](https://www.rcsb.org/structure/8JFL), [8XY7](https://www.rcsb.org/structure/8XY7), [8XYA](https://www.rcsb.org/structure/8XYA), [8XYB](https://www.rcsb.org/structure/8XYB), [8Z5M](https://www.rcsb.org/structure/8Z5M).

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

*Describes the biological roles of PHKA1 (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}

PHKA1 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, positive regulation of glycogen catabolic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-25.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2021–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-08-25 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-05-12 |

## Associated conditions {#conditions}

[glycogen storage disease IXd](https://sugi.bio/atlas/disease/glycogen-storage-disease-ixd/).

**Reported phenotype names (ClinVar):** Glycogen storage disease IXd, PHKA1-related disorder, GSD IXd, Muscle Phosphorylase Kinase Deficiency, PHKA1-related condition.

## Similar variants {#similar}

Related PHKA1 variant pages (same residue, condition, or type): [PHKA1 c.2137+1G>A](/variant/phka1-c-2137-plus-1g-a), [PHKA1 c.2527-1G>T](/variant/phka1-c-2527-minus-1g-t), [PHKA1 c.2606+1G>A](/variant/phka1-c-2606-plus-1g-a), [PHKA1 c.537+1G>A](/variant/phka1-c-537-plus-1g-a), [PHKA1 p.Arg298Ter](/variant/phka1-p-arg298ter), [PHKA1 p.Arg392Ter](/variant/phka1-p-arg392ter), [PHKA1 p.Arg739Ter](/variant/phka1-p-arg739ter), [PHKA1 p.Arg863Ter](/variant/phka1-p-arg863ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 2039042). 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.*