Is PHKA1 p.Val380Phe (c.1138G>T) pathogenic?

PHKA1 p.Val380Phe (c.1138G>T) is classified Uncertain significance in PHKA1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-11). AlphaMissense: ambiguous (0.5072); Very rare (popmax 0.00199%, nfe); Associated with glycogen storage disease IXd.

What condition is associated with PHKA1 p.Val380Phe (c.1138G>T)?

PHKA1 p.Val380Phe (c.1138G>T) is associated with glycogen storage disease IXd (ClinVar).

How common is PHKA1 p.Val380Phe (c.1138G>T) in the general population?

PHKA1 p.Val380Phe (c.1138G>T) is very rare (popmax 0.00199%, nfe) (gnomAD).

What do computational predictors say about PHKA1 p.Val380Phe (c.1138G>T)?

AlphaMissense predicts ambiguous (score 0.5072) — an in-silico prediction, not a clinical call.

PHKA1 p.Val380Phe

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.1138G>T · VCV3715824

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5072 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00199%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

glycogen storage disease IXd

Computational evidence

Protein change
AlphaMissense	0.5072	ambiguous
REVEL	0.891	moderately pathogenic-leaning
SaProt	LLR -12.82	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 79 kb · p 1.5e-09 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00199% European (non-Finnish) · 16/802,603 alleles

Filtering AF 0.00118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000955%

Overall 0.00154% 17/1,106,968 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00226%	44,216
European (non-Finnish)grpmax	0.00199%	50,163

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val380Phe
Coding: c.1138G>T
MANE Select: NM_002637
Type: single nucleotide variant
Location: chrX:72652651 (GRCh38)
Structure: AlphaFold pLDDT 81.84 · 10 PDB
Residue 380: 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 p.Val380= Likely benign ★ same residue
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

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-val380phe (accessed [today's date]).

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