Is PYGL p.Arg321His (c.962G>A) pathogenic?

PYGL p.Arg321His (c.962G>A) is classified Benign/Likely benign in PYGL (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-11). AlphaMissense: likely benign (0.0845); Low-frequency (popmax 2.9%, afr); Associated with glycogen storage disease VI.

What condition is associated with PYGL p.Arg321His (c.962G>A)?

PYGL p.Arg321His (c.962G>A) is associated with glycogen storage disease VI (ClinVar).

How common is PYGL p.Arg321His (c.962G>A) in the general population?

PYGL p.Arg321His (c.962G>A) is low-frequency (popmax 2.9%, afr) (gnomAD).

What do computational predictors say about PYGL p.Arg321His (c.962G>A)?

AlphaMissense predicts likely benign (score 0.0845) — an in-silico prediction, not a clinical call.

PYGL p.Arg321His

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.962G>A · rs116465563 · VCV258850

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0845 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.9%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease VI

Computational evidence

Protein change
AlphaMissense	0.0845	likely benign
REVEL	0.179	moderately benign-leaning
SaProt	LLR -6.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.31	GERP -3.5
Regional constraint	o/e 0.96	unconstrained · MANE · 39 kb · p 0.2 · regional, not allelic
Overall
CADD	13.62	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 2.9% African / African-American · 2,175/75,042 alleles

Filtering AF 2.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.76%

Overall 0.147% 2,371/1,614,200 alleles · low-frequency exomes 1,143/1,461,860 · genomes 1,228/152,340 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.9%	35
Remaining individualsnot grpmax-eligible	0.131%	762
Admixed American	0.125%	800
Middle Eastern	0.066%	1,516
South Asian	0.00549%	18,217
European (non-Finnish)	0.00246%	40,691
East Asian	0.00223%	44,888

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.Arg321His
Coding: c.962G>A
MANE Select: NM_002863
dbSNP: rs116465563
Type: single nucleotide variant
Location: chr14:50916999 (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.Arg321Cys 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-arg321his (accessed [today's date]).

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