Is PYGL p.Pro737Ser (c.2209C>T) pathogenic?

PYGL p.Pro737Ser (c.2209C>T) is classified Uncertain significance in PYGL (ClinVar, Single submitter, 1 submitter; last evaluated 2018-10-31). AlphaMissense: likely benign (0.1518); Ultra-rare (popmax 0.0738%, sas); Associated with glycogen storage disease VI.

What condition is associated with PYGL p.Pro737Ser (c.2209C>T)?

PYGL p.Pro737Ser (c.2209C>T) is associated with glycogen storage disease VI (ClinVar).

How common is PYGL p.Pro737Ser (c.2209C>T) in the general population?

PYGL p.Pro737Ser (c.2209C>T) is ultra-rare (popmax 0.0738%, sas) (gnomAD).

What do computational predictors say about PYGL p.Pro737Ser (c.2209C>T)?

AlphaMissense predicts likely benign (score 0.1518) — an in-silico prediction, not a clinical call.

PYGL p.Pro737Ser

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

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

c.2209C>T · rs759925909 · VCV638850

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1518 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0738%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

glycogen storage disease VI

Computational evidence

Protein change
AlphaMissense	0.1518	likely benign
REVEL	0.583	indeterminate
SaProt	LLR -9.16	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 39 kb · p 0.2 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0738% South Asian · 66/89,482 alleles

Filtering AF 0.0594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0542%

Overall 0.0046% 69/1,501,268 alleles · ultra-rare exomes 67/1,352,618 · genomes 2/148,650 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0738%	1,356
Middle Eastern	0.0178%	5,616
Remaining individualsnot grpmax-eligible	0.00356%	28,069

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: PYGL
Protein: p.Pro737Ser
Coding: c.2209C>T
MANE Select: NM_002863
dbSNP: rs759925909
Type: single nucleotide variant
Location: chr14:50908924 (GRCh38)
Gene constraint: LOEUF 1.048 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.87 · 19 PDB
Residue 737: an α-helix

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

Disease context

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

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

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

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PYGL c.1768+1G>A Pathogenic ★★ same condition
PYGL c.772+1G>A Pathogenic/Likely pathogenic ★★ same condition
PYGL p.Arg576Ter Pathogenic ★★ same condition
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PYGL p.Gln577Ter Pathogenic/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/pygl-p-pro737ser (accessed [today's date]).

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