Is PYGL p.Pro382Leu (c.1145C>T) pathogenic?

PYGL p.Pro382Leu (c.1145C>T) is classified Conflicting classifications of pathogenicity in PYGL (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-02-01). AlphaMissense: likely pathogenic (0.6351); Rare (popmax 0.677%, nfe); Associated with glycogen storage disease VI.

What condition is associated with PYGL p.Pro382Leu (c.1145C>T)?

PYGL p.Pro382Leu (c.1145C>T) is associated with glycogen storage disease VI (ClinVar).

How common is PYGL p.Pro382Leu (c.1145C>T) in the general population?

PYGL p.Pro382Leu (c.1145C>T) is rare (popmax 0.677%, nfe) (gnomAD).

What do computational predictors say about PYGL p.Pro382Leu (c.1145C>T)?

AlphaMissense predicts likely pathogenic (score 0.6351) — an in-silico prediction, not a clinical call.

PYGL p.Pro382Leu

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.1145C>T · rs143759519 · VCV522775

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

AlphaMissense

likely pathogenic

0.6351 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.677%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease VI

Computational evidence

Protein change
AlphaMissense	0.6351	likely pathogenic
REVEL	0.924	moderately pathogenic-leaning
SaProt	LLR -12.04	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 39 kb · p 0.2 · regional, not allelic
Overall
CADD	29.6	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 0.677% European (non-Finnish) · 7,992/1,180,026 alleles

Filtering AF 0.665% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.66%

Overall 0.547% 8,824/1,614,214 alleles · rare exomes 8,175/1,461,854 · genomes 649/152,360 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.21%	83
European (non-Finnish)grpmax	0.677%	148
Remaining individualsnot grpmax-eligible	0.414%	241
Finnishnot grpmax-eligible	0.32%	312
South Asian	0.155%	646
Admixed American	0.14%	715
Middle Eastern	0.132%	758
Ashkenazi Jewishnot grpmax-eligible	0.128%	779
African / African-American	0.115%	873

Amish 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: PYGL
Protein: p.Pro382Leu
Coding: c.1145C>T
MANE Select: NM_002863
dbSNP: rs143759519
Type: single nucleotide variant
Location: chr14:50915919 (GRCh38)
Gene constraint: LOEUF 1.048 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.87 · 19 PDB
Residue 382: 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
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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-pro382leu (accessed [today's date]).

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