Is PGM3 p.Arg174Ter (c.520C>T) pathogenic?

PGM3 p.Arg174Ter (c.520C>T) is classified Pathogenic in PGM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-18). Very rare (popmax 0.0022%, sas); Associated with immunodeficiency 23.

What condition is associated with PGM3 p.Arg174Ter (c.520C>T)?

PGM3 p.Arg174Ter (c.520C>T) is associated with immunodeficiency 23 (ClinVar).

How common is PGM3 p.Arg174Ter (c.520C>T) in the general population?

PGM3 p.Arg174Ter (c.520C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

How is PGM3-CDG inherited?

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

PGM3 p.Arg174Ter

c.520C>T · rs762678772 · VCV541844

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

immunodeficiency 23

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 13
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 0.54, phastCons 1
Overall
CADD	35.0	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 0.0022% South Asian · 2/91,078 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.00031% 5/1,613,706 alleles · very rare exomes 4/1,461,628 · genomes 1/152,078 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,539
Remaining individualsnot grpmax-eligible	0.0016%	62,472
African / African-American	0.00134%	74,866
European (non-Finnish)	8.48e-05%	1,179,814

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.Arg174Ter
Coding: c.520C>T
MANE Select: NM_015599
dbSNP: rs762678772
Type: single nucleotide variant
Location: chr6:83182916 (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.Arg174Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PGM3 p.Arg174= Likely benign ★ same residue
PGM3 c.-2-185C>T Pathogenic/Likely pathogenic ★★ same condition
PGM3 p.Arg104Ter Pathogenic/Likely pathogenic ★★ same condition
PGM3 p.Asn246Ser Pathogenic/Likely pathogenic ★★ same condition
PGM3 p.Gln22Ter Pathogenic/Likely pathogenic ★★ same condition
PGM3 p.Gln262Ter Pathogenic/Likely pathogenic ★★ same condition
PGM3 c.389+6G>A 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/pgm3-p-arg174ter (accessed [today's date]).

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