Is PYGL p.Val222Ile (c.664G>A) pathogenic?

PYGL p.Val222Ile (c.664G>A) is classified Benign in PYGL (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0907); Common (popmax 18.5%, afr) — too common for a highly-penetrant pathogenic allele; Associated with glycogen storage disease VI.

What condition is associated with PYGL p.Val222Ile (c.664G>A)?

PYGL p.Val222Ile (c.664G>A) is associated with glycogen storage disease VI (ClinVar).

What do computational predictors say about PYGL p.Val222Ile (c.664G>A)?

AlphaMissense predicts likely benign (score 0.0907) — an in-silico prediction, not a clinical call.

PYGL p.Val222Ile

Q: How common is PYGL p.Val222Ile (c.664G>A) in the general population?

PYGL p.Val222Ile (c.664G>A) is common (popmax 18.5%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.664G>A · rs946616 · VCV258846

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0907 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 18.5%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

glycogen storage disease VI

Computational evidence

Protein change
AlphaMissense	0.0907	likely benign
REVEL	0.383	indeterminate
SaProt	LLR -7.93	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 2.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 39 kb · p 0.2 · regional, not allelic
Overall
CADD	23.1	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 18.5% African / African-American · 13,835/74,846 alleles

Filtering AF 18.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 18.1%

Overall 6.79% 109,408/1,610,242 alleles · common exomes 94,945/1,458,038 · genomes 14,463/152,204 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	18.5%	5
Amishnot grpmax-eligible	11.3%	9
South Asian	9.27%	11
Ashkenazi Jewishnot grpmax-eligible	8.99%	11
Middle Eastern	6.8%	15
Remaining individualsnot grpmax-eligible	6.61%	15
European (non-Finnish)	6.16%	16
Finnishnot grpmax-eligible	5.63%	18
Admixed American	3.78%	26
East Asian	3.34%	30

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.Val222Ile
Coding: c.664G>A
MANE Select: NM_002863
dbSNP: rs946616
Type: single nucleotide variant
Location: chr14:50921064 (GRCh38)
Gene constraint: LOEUF 1.048 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.87 · 19 PDB
Residue 222: a UniProt-annotated variant site (in); 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-val222ile (accessed [today's date]).

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