Is PYGM p.Arg34Trp (c.100C>T) pathogenic?

PYGM p.Arg34Trp (c.100C>T) is classified Uncertain significance in PYGM (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-09). AlphaMissense: likely pathogenic (0.6031); Ultra-rare (popmax 0.0111%, eas); Associated with glycogen storage disease V.

What condition is associated with PYGM p.Arg34Trp (c.100C>T)?

PYGM p.Arg34Trp (c.100C>T) is associated with glycogen storage disease V (ClinVar).

How common is PYGM p.Arg34Trp (c.100C>T) in the general population?

PYGM p.Arg34Trp (c.100C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about PYGM p.Arg34Trp (c.100C>T)?

AlphaMissense predicts likely pathogenic (score 0.6031) — an in-silico prediction, not a clinical call.

PYGM p.Arg34Trp

Q: How is Glycogen storage disease due to muscle glycogen phosphorylase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.100C>T · rs531748591 · VCV1254381

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.6031 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease V

Computational evidence

Protein change
AlphaMissense	0.6031	likely pathogenic
REVEL	0.757	pathogenic-leaning
SaProt	LLR -12.13	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 6.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 13 kb · p 0.00017 · regional, not allelic
Overall
CADD	31.0	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 0.0111% East Asian · 5/44,892 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00361%

Overall 0.00545% 88/1,614,096 alleles · ultra-rare exomes 76/1,461,882 · genomes 12/152,214 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,289
East Asiangrpmax	0.0111%	8,978
Admixed American	0.01%	10,003
Remaining individualsnot grpmax-eligible	0.0064%	15,622
European (non-Finnish)	0.005%	20,001
African / African-American	0.004%	24,981
South Asian	0.0022%	45,542

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: PYGM
Protein: p.Arg34Trp
Coding: c.100C>T
MANE Select: NM_005609
dbSNP: rs531748591
Type: single nucleotide variant
Location: chr11:64759799 (GRCh38)
Gene constraint: LOEUF 0.962 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.41 · 1 PDB
Residue 34: an α-helix

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

Disease context

glycogen storage disease V — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glycogen storage disease due to muscle glycogen phosphorylase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

Similar variants

PYGM p.Arg34= Conflicting classifications of pathogenicity ★ same residue
PYGM p.Arg34Gln Uncertain significance ★ ⚠ same residue
PYGM c.1092+1G>A Likely pathogenic ★★ same condition
PYGM c.1092+1G>C Likely pathogenic ★★ same condition
PYGM c.1239+1G>A Pathogenic/Likely pathogenic ★★ same condition
PYGM c.1240-2A>G Likely pathogenic ★★ same condition
PYGM c.1403+1G>A Pathogenic ★★ same condition
PYGM c.1768+1G>A 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/pygm-p-arg34trp (accessed [today's date]).

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