Is PGM3 p.Ser133fs (c.398_413del) pathogenic?

PGM3 p.Ser133fs (c.398413del) is classified Pathogenic in PGM3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-01). Very rare (popmax 0.000513%, nfe); Associated with immunodeficiency 23.

What condition is associated with PGM3 p.Ser133fs (c.398_413del)?

PGM3 p.Ser133fs (c.398_413del) is associated with immunodeficiency 23 (ClinVar).

How common is PGM3 p.Ser133fs (c.398_413del) in the general population?

PGM3 p.Ser133fs (c.398_413del) is very rare (popmax 0.000513%, nfe) (gnomAD).

How is PGM3-CDG inherited?

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

PGM3 p.Ser133fs

c.398_413del · rs1404084330 · VCV504123

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000513%, nfe)

Conditions

immunodeficiency 23

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -4.8	GERP -4.2
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000513% European (non-Finnish) · 6/1,169,722 alleles

Filtering AF 0.000185% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000374% 6/1,602,298 alleles · very rare exomes 5/1,450,102 · genomes 1/152,196 · 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: PGM3
Protein: p.Ser133fs
Coding: c.398_413del
MANE Select: NM_015599
dbSNP: rs1404084330
Type: Deletion
Location: chr6:83187052 (GRCh38)
Gene constraint: LOEUF 0.962 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 95.54

Full PGM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency 23 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For PGM3-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

PGM3 p.Leu452fs Pathogenic ★★ same condition
PGM3 p.Lys54fs Pathogenic ★★ same condition
PGM3 p.Met385fs Pathogenic/Likely pathogenic ★★ same condition
PGM3 c.390-232_417del Likely pathogenic ★ same condition
PGM3 c.-2-238del Pathogenic ★ same condition
PGM3 c.-2-242_-2-241del Pathogenic ★ same condition
PGM3 p.Arg127fs Pathogenic ★ same condition
PGM3 p.Asp418_Ala419insTer 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/pgm3-p-ser133fs (accessed [today's date]).

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