Is PYGL p.Arg161Trp (c.481C>T) pathogenic?

PYGL p.Arg161Trp (c.481C>T) is classified Uncertain significance in PYGL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-12). AlphaMissense: likely pathogenic (0.9021); Ultra-rare (popmax 0.025%, amr); Associated with glycogen storage disease VI.

What condition is associated with PYGL p.Arg161Trp (c.481C>T)?

PYGL p.Arg161Trp (c.481C>T) is associated with glycogen storage disease VI (ClinVar).

How common is PYGL p.Arg161Trp (c.481C>T) in the general population?

PYGL p.Arg161Trp (c.481C>T) is ultra-rare (popmax 0.025%, amr) (gnomAD).

What do computational predictors say about PYGL p.Arg161Trp (c.481C>T)?

AlphaMissense predicts likely pathogenic (score 0.9021) — an in-silico prediction, not a clinical call.

PYGL p.Arg161Trp

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.481C>T · rs749811385 · VCV1163946

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9021 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease VI

Computational evidence

Protein change
AlphaMissense	0.9021	likely pathogenic
REVEL	0.925	moderately pathogenic-leaning
SaProt	LLR -14.13	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 39 kb · p 0.2 · regional, not allelic
Overall
CADD	34.0	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 0.025% Admixed American · 15/59,982 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.00167% 27/1,613,732 alleles · ultra-rare exomes 26/1,461,726 · genomes 1/152,006 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.025%	3,999
Remaining individualsnot grpmax-eligible	0.0064%	15,621
European (non-Finnish)	0.000678%	147,489

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.Arg161Trp
Coding: c.481C>T
MANE Select: NM_002863
dbSNP: rs749811385
Type: single nucleotide variant
Location: chr14:50931720 (GRCh38)
Gene constraint: LOEUF 1.048 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.87 · 19 PDB

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 p.Arg161Gln Uncertain significance ★ ⚠ same residue
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

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-arg161trp (accessed [today's date]).

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