Is PYGL p.Pro250Leu (c.749C>T) pathogenic?

PYGL p.Pro250Leu (c.749C>T) is classified Uncertain significance in PYGL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-08-01). AlphaMissense: ambiguous (0.4791); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PYGL p.Pro250Leu (c.749C>T)?

PYGL p.Pro250Leu (c.749C>T) is associated with Inborn genetic diseases, glycogen storage disease VI (ClinVar).

How common is PYGL p.Pro250Leu (c.749C>T) in the general population?

PYGL p.Pro250Leu (c.749C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about PYGL p.Pro250Leu (c.749C>T)?

AlphaMissense predicts ambiguous (score 0.4791) — an in-silico prediction, not a clinical call.

PYGL p.Pro250Leu

c.749C>T · rs1472614445 · VCV1029652

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4791 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4791	ambiguous
REVEL	0.745	pathogenic-leaning
SaProt	LLR -13.56	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 39 kb · p 0.2 · regional, not allelic
Overall
CADD	28.4	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 8.48e-05% European (non-Finnish) · 1/1,179,902 alleles

Overall 6.2e-05% 1/1,614,040 alleles · very rare exomes 1/1,461,726 · genomes 0/152,314 · 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.Pro250Leu
Coding: c.749C>T
MANE Select: NM_002863
dbSNP: rs1472614445
Type: single nucleotide variant
Location: chr14:50920979 (GRCh38)
Gene constraint: LOEUF 1.048 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.87 · 19 PDB
Residue 250: an α-helix

Full PYGL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: glycogen storage disease VI

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-pro250leu (accessed [today's date]).

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