Is PHKA1 p.Ser405Phe (c.1214C>T) pathogenic?

PHKA1 p.Ser405Phe (c.1214C>T) is classified Uncertain significance in PHKA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-06). AlphaMissense: likely pathogenic (0.9961); Ultra-rare (popmax 0.0372%, amr); Associated with glycogen storage disease IXd.

What condition is associated with PHKA1 p.Ser405Phe (c.1214C>T)?

PHKA1 p.Ser405Phe (c.1214C>T) is associated with glycogen storage disease IXd (ClinVar).

How common is PHKA1 p.Ser405Phe (c.1214C>T) in the general population?

PHKA1 p.Ser405Phe (c.1214C>T) is ultra-rare (popmax 0.0372%, amr) (gnomAD).

What do computational predictors say about PHKA1 p.Ser405Phe (c.1214C>T)?

AlphaMissense predicts likely pathogenic (score 0.9961) — an in-silico prediction, not a clinical call.

PHKA1 p.Ser405Phe

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.1214C>T · rs199582889 · VCV1499851

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9961 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0372%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease IXd

Computational evidence

Protein change
AlphaMissense	0.9961	likely pathogenic · top 2% in PHKA1
REVEL	0.965	strongly pathogenic-leaning
SaProt	LLR -14.14	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.66 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 79 kb · p 1.5e-09 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0372% Admixed American · 17/45,709 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0194%

Overall 0.00161% 19/1,182,272 alleles · ultra-rare exomes 17/1,070,618 · genomes 2/111,654 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0372%	2,689
Remaining individualsnot grpmax-eligible	0.00214%	46,791
African / African-American	0.00176%	56,658

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.Ser405Phe
Coding: c.1214C>T
MANE Select: NM_002637
dbSNP: rs199582889
Type: single nucleotide variant
Location: chrX:72652575 (GRCh38)
Structure: AlphaFold pLDDT 81.84 · 10 PDB
Residue 405: an α-helix

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-ser405phe (accessed [today's date]).

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