Is PYGM p.Leu522Arg (c.1565T>G) pathogenic?

PYGM p.Leu522Arg (c.1565T>G) is classified Uncertain significance in PYGM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely pathogenic (0.9802); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with PYGM p.Leu522Arg (c.1565T>G)?

PYGM p.Leu522Arg (c.1565T>G) is associated with Inborn genetic diseases (ClinVar).

How common is PYGM p.Leu522Arg (c.1565T>G) in the general population?

PYGM p.Leu522Arg (c.1565T>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PYGM p.Leu522Arg (c.1565T>G)?

AlphaMissense predicts likely pathogenic (score 0.9802) — an in-silico prediction, not a clinical call.

PYGM p.Leu522Arg

c.1565T>G · VCV4148724

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9802 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9802	likely pathogenic
REVEL	0.955	strongly pathogenic-leaning
SaProt	LLR -16.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 13 kb · p 0.00017 · regional, not allelic
Overall
CADD	28.2	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 0.00133% African / African-American · 1/75,076 alleles

Overall 6.19e-05% 1/1,614,254 alleles · very rare exomes 1/1,461,880 · genomes 0/152,374 · 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: PYGM
Protein: p.Leu522Arg
Coding: c.1565T>G
MANE Select: NM_005609
Type: single nucleotide variant
Location: chr11:64752458 (GRCh38)
Gene constraint: LOEUF 0.962 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.41 · 1 PDB
Residue 522: a UniProt-annotated variant site (in gsd5); an α-helix

Full PYGM 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

Similar variants

PYGM p.Ala448Thr Uncertain significance ★★ ⚠ same condition
PYGM p.Arg17His Uncertain significance ★★ ⚠ same condition
PYGM p.Arg310Cys Uncertain significance ★★ ⚠ same condition
PYGM p.Arg310His Uncertain significance ★★ ⚠ same condition
PYGM p.Arg428His Uncertain significance ★★ ⚠ same condition
PYGM p.Arg50Gln Uncertain significance ★★ same condition
PYGM p.Arg640Cys Uncertain significance ★★ ⚠ same condition
PYGM p.Arg67Cys Uncertain significance ★★ ⚠ 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/pygm-p-leu522arg (accessed [today's date]).

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