Is PYGL p.Lys642Thr (c.1925A>C) pathogenic?

PYGL p.Lys642Thr (c.1925A>C) is classified Uncertain significance in PYGL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-20). AlphaMissense: ambiguous (0.5046); Very rare (popmax 0.00666%, afr); Associated with glycogen storage disease VI.

What condition is associated with PYGL p.Lys642Thr (c.1925A>C)?

PYGL p.Lys642Thr (c.1925A>C) is associated with glycogen storage disease VI (ClinVar).

How common is PYGL p.Lys642Thr (c.1925A>C) in the general population?

PYGL p.Lys642Thr (c.1925A>C) is very rare (popmax 0.00666%, afr) (gnomAD).

What do computational predictors say about PYGL p.Lys642Thr (c.1925A>C)?

AlphaMissense predicts ambiguous (score 0.5046) — an in-silico prediction, not a clinical call.

PYGL p.Lys642Thr

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.1925A>C · rs556404496 · VCV2910567

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5046 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

glycogen storage disease VI

Computational evidence

Protein change
AlphaMissense	0.5046	ambiguous
REVEL	0.939	strongly pathogenic-leaning
SaProt	LLR -12.64	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.2	GERP 0.83, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 39 kb · p 0.2 · regional, not allelic
Overall
CADD	27.0	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 0.00666% African / African-American · 5/75,056 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00031% 5/1,614,192 alleles · very rare exomes 3/1,461,864 · genomes 2/152,328 · 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: PYGL
Protein: p.Lys642Thr
Coding: c.1925A>C
MANE Select: NM_002863
dbSNP: rs556404496
Type: single nucleotide variant
Location: chr14:50911774 (GRCh38)
Gene constraint: LOEUF 1.048 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.87 · 19 PDB
Residue 642: a β-strand

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

PYGL c.1404-1G>A Pathogenic/Likely pathogenic ★★ same condition
PYGL c.1620+1G>A Pathogenic/Likely pathogenic ★★ same condition
PYGL c.1620+1G>C Pathogenic ★★ same condition
PYGL c.1768+1G>A Pathogenic ★★ same condition
PYGL c.772+1G>A Pathogenic/Likely pathogenic ★★ same condition
PYGL p.Arg576Ter Pathogenic ★★ same condition
PYGL p.Arg94Ter Pathogenic ★★ same condition
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-lys642thr (accessed [today's date]).

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