Is PYGM p.Phe469Ser (c.1406T>C) pathogenic?

PYGM p.Phe469Ser (c.1406T>C) is classified Uncertain significance in PYGM (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-21). AlphaMissense: likely pathogenic (0.9829); Very rare (popmax 8.53e-05%, nfe); Associated with glycogen storage disease V.

What condition is associated with PYGM p.Phe469Ser (c.1406T>C)?

PYGM p.Phe469Ser (c.1406T>C) is associated with glycogen storage disease V (ClinVar).

How common is PYGM p.Phe469Ser (c.1406T>C) in the general population?

PYGM p.Phe469Ser (c.1406T>C) is very rare (popmax 8.53e-05%, nfe) (gnomAD).

What do computational predictors say about PYGM p.Phe469Ser (c.1406T>C)?

AlphaMissense predicts likely pathogenic (score 0.9829) — an in-silico prediction, not a clinical call.

PYGM p.Phe469Ser

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

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

c.1406T>C · VCV3600047

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9829 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.53e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease V

Computational evidence

Protein change
AlphaMissense	0.9829	likely pathogenic
REVEL	0.956	strongly pathogenic-leaning
SaProt	LLR -15.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 13 kb · p 0.00017 · regional, not allelic
Overall
CADD	28.8	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 8.53e-05% European (non-Finnish) · 1/1,172,524 alleles

Overall 6.23e-05% 1/1,605,634 alleles · very rare exomes 0/1,453,460 · genomes 1/152,174 · 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: PYGM
Protein: p.Phe469Ser
Coding: c.1406T>C
MANE Select: NM_005609
Type: single nucleotide variant
Location: chr11:64753185 (GRCh38)
Gene constraint: LOEUF 0.962 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.41 · 1 PDB
Residue 469: a UniProt-annotated variant site (in gsd5); a turn

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

Disease context

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

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

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

Similar variants

PYGM c.1092+1G>A Likely pathogenic ★★ same condition
PYGM c.1092+1G>C Likely pathogenic ★★ same condition
PYGM c.1239+1G>A Pathogenic/Likely pathogenic ★★ same condition
PYGM c.1240-2A>G Likely pathogenic ★★ same condition
PYGM c.1403+1G>A Pathogenic ★★ same condition
PYGM c.1768+1G>A Pathogenic/Likely pathogenic ★★ same condition
PYGM c.1768+2T>G Pathogenic/Likely pathogenic ★★ same condition
PYGM c.1827+1G>C 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/pygm-p-phe469ser (accessed [today's date]).

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