Is PGK1 p.Ser4Phe (c.11C>T) pathogenic?

PGK1 p.Ser4Phe (c.11C>T) is classified Uncertain significance in PGK1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-30). AlphaMissense: ambiguous (0.5145); Very rare (popmax 0.000112%, nfe); Associated with glycogen storage disease due to phosphoglycerate kinase 1 deficiency.

What condition is associated with PGK1 p.Ser4Phe (c.11C>T)?

PGK1 p.Ser4Phe (c.11C>T) is associated with glycogen storage disease due to phosphoglycerate kinase 1 deficiency (ClinVar).

How common is PGK1 p.Ser4Phe (c.11C>T) in the general population?

PGK1 p.Ser4Phe (c.11C>T) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about PGK1 p.Ser4Phe (c.11C>T)?

AlphaMissense predicts ambiguous (score 0.5145) — an in-silico prediction, not a clinical call.

PGK1 p.Ser4Phe

Q: How is Glycogen storage disease due to phosphoglycerate kinase 1 deficiency inherited?

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

c.11C>T · rs2078257508 · VCV1308105

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5145 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Conditions

glycogen storage disease due to phosphoglycerate kinase 1 deficiency

Computational evidence

Protein change
AlphaMissense	0.5145	ambiguous
REVEL	0.599	indeterminate
SaProt	LLR -8.35	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 2.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 14 kb · p 0.71 · regional, not allelic
Overall
CADD	24.3	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 0.000112% European (non-Finnish) · 1/890,165 alleles

Overall 8.29e-05% 1/1,206,154 alleles · very rare exomes 1/1,091,989 · genomes 0/114,165 · joint denominator

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: PGK1
Protein: p.Ser4Phe
Coding: c.11C>T
MANE Select: NM_000291
dbSNP: rs2078257508
Type: single nucleotide variant
Location: chrX:78104351 (GRCh38)
Structure: AlphaFold pLDDT 96.48 · 30 PDB
Residue 4: a modified residue (phosphoserine); an α-helix

Full PGK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

glycogen storage disease due to phosphoglycerate kinase 1 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glycogen storage disease due to phosphoglycerate kinase 1 deficiency (Orphanet):

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

Similar variants

PGK1 p.Asp164Val Pathogenic ★★ same condition
PGK1 p.Ala109Asp Uncertain significance ★★ ⚠ same condition
PGK1 p.Ala296Val Uncertain significance ★★ ⚠ same condition
PGK1 p.Ala55Asp Uncertain significance ★★ ⚠ same condition
PGK1 p.Arg151Gln Uncertain significance ★★ same condition
PGK1 p.Arg330Trp Uncertain significance ★★ ⚠ same condition
PGK1 p.Asn163Ser Uncertain significance ★★ ⚠ same condition
PGK1 p.Asn26Ser Uncertain significance ★★ ⚠ 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/pgk1-p-ser4phe (accessed [today's date]).

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