Is PYGL p.Val231Met (c.691G>A) pathogenic?

PYGL p.Val231Met (c.691G>A) is classified Conflicting classifications of pathogenicity in PYGL (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-20). AlphaMissense: ambiguous (0.5462); Ultra-rare (popmax 0.02%, eas); Associated with glycogen storage disease VI.

What condition is associated with PYGL p.Val231Met (c.691G>A)?

PYGL p.Val231Met (c.691G>A) is associated with glycogen storage disease VI (ClinVar).

How common is PYGL p.Val231Met (c.691G>A) in the general population?

PYGL p.Val231Met (c.691G>A) is ultra-rare (popmax 0.02%, eas) (gnomAD).

What do computational predictors say about PYGL p.Val231Met (c.691G>A)?

AlphaMissense predicts ambiguous (score 0.5462) — an in-silico prediction, not a clinical call.

PYGL p.Val231Met

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.691G>A · rs148378112 · VCV313330

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5462 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

glycogen storage disease VI

Computational evidence

Protein change
AlphaMissense	0.5462	ambiguous
REVEL	0.683	pathogenic-leaning
SaProt	LLR -12.97	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 39 kb · p 0.2 · regional, not allelic
Overall
CADD	24.7	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 0.02% East Asian · 9/44,896 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00779%

Overall 0.0193% 312/1,613,998 alleles · ultra-rare exomes 282/1,461,838 · genomes 30/152,160 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.73%	137
Remaining individualsnot grpmax-eligible	0.0448%	2,232
East Asiangrpmax	0.02%	4,988
Middle Eastern	0.0165%	6,078
Admixed American	0.00667%	14,997
European (non-Finnish)	0.00415%	24,082
African / African-American	0.004%	24,971
South Asian	0.0022%	45,541

Ashkenazi Jewish 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.Val231Met
Coding: c.691G>A
MANE Select: NM_002863
dbSNP: rs148378112
Type: single nucleotide variant
Location: chr14:50921037 (GRCh38)
Gene constraint: LOEUF 1.048 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.87 · 19 PDB
Residue 231: 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-val231met (accessed [today's date]).

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