Is PHKA1 p.Phe181= (c.543C>T) pathogenic?

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.

What condition is associated with PHKA1 p.Phe181= (c.543C>T)?

PHKA1 p.Phe181= (c.543C>T) is associated with glycogen storage disease IXd (ClinVar).

How common is PHKA1 p.Phe181= (c.543C>T) in the general population?

PHKA1 p.Phe181= (c.543C>T) is ultra-rare (popmax 0.0141%, afr) (gnomAD).

PHKA1 p.Phe181=

Q: How is Glycogen storage disease due to muscle phosphorylase kinase deficiency inherited?

Typically Autosomal recessive, X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.543C>T · rs781909169 · VCV2039042

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0141%, afr)

Conditions

glycogen storage disease IXd

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP -4.7	GERP -3.6
Overall
CADD	0.101	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0141% African / African-American · 8/56,541 alleles

Filtering AF 0.00696% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00508%

Overall 0.00442% 53/1,198,583 alleles · ultra-rare exomes 42/1,088,011 · genomes 11/110,572 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0141%	7,068
Admixed American	0.011%	9,110
Remaining individualsnot grpmax-eligible	0.00635%	15,758
European (non-Finnish)	0.00406%	24,609
South Asian	0.00178%	56,318

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: PHKA1
Protein: p.Phe181=
Coding: c.543C>T
MANE Select: NM_002637
dbSNP: rs781909169
Type: single nucleotide variant
Location: chrX:72676145 (GRCh38)
Structure: AlphaFold pLDDT 81.84 · 10 PDB

Full PHKA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

glycogen storage disease IXd — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glycogen storage disease due to muscle phosphorylase kinase deficiency (Orphanet):

Inheritance: Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult

Similar variants

PHKA1 c.2137+1G>A Likely pathogenic ★★ same condition
PHKA1 c.2527-1G>T Likely pathogenic ★★ same condition
PHKA1 c.2606+1G>A Pathogenic/Likely pathogenic ★★ same condition
PHKA1 c.537+1G>A Likely pathogenic ★★ same condition
PHKA1 p.Arg298Ter Pathogenic ★★ same condition
PHKA1 p.Arg392Ter Pathogenic/Likely pathogenic ★★ same condition
PHKA1 p.Arg739Ter Likely pathogenic ★★ same condition
PHKA1 p.Arg863Ter 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/phka1-p-phe181 (accessed [today's date]).

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