Is PGM3 p.Glu427= (c.1281A>G) pathogenic?

PGM3 p.Glu427= (c.1281A>G) is classified Benign/Likely benign in PGM3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 57%, afr) — too common for a highly-penetrant pathogenic allele; Associated with immunodeficiency 23.

What condition is associated with PGM3 p.Glu427= (c.1281A>G)?

PGM3 p.Glu427= (c.1281A>G) is associated with immunodeficiency 23 (ClinVar).

How is PGM3-CDG inherited?

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

PGM3 p.Glu427=

Q: How common is PGM3 p.Glu427= (c.1281A>G) in the general population?

PGM3 p.Glu427= (c.1281A>G) is common (popmax 57%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1281A>G · rs542948 · VCV672119

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 57%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

immunodeficiency 23

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.022	GERP -2.6, phastCons 0.85
Overall
CADD	7.519	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 57% African / African-American · 42,665/74,886 alleles

Filtering AF 56.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 56.3%

Overall 27.4% 442,184/1,612,468 alleles · common exomes 389,422/1,460,388 · genomes 52,762/152,080 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	57%	2
East Asian	30.9%	3
Remaining individualsnot grpmax-eligible	27.9%	4
Admixed American	27.2%	4
Finnishnot grpmax-eligible	26.5%	4
European (non-Finnish)	26%	4
South Asian	23.6%	4
Middle Eastern	21.6%	5
Ashkenazi Jewishnot grpmax-eligible	19.5%	5
Amishnot grpmax-eligible	16.6%	6

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.Glu427=
Coding: c.1281A>G
MANE Select: NM_015599
dbSNP: rs542948
Type: single nucleotide variant
Location: chr6:83172021 (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.Glu427Asp Uncertain significance ★ ⚠ 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
PGM3 c.-2-226T>C 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-glu427 (accessed [today's date]).

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