Is PGM1 p.Arg405Ser (c.1213C>A) pathogenic?

PGM1 p.Arg405Ser (c.1213C>A) is classified Uncertain significance in PGM1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-11). AlphaMissense: likely pathogenic (0.7508); Ultra-rare (popmax 0.0681%, sas); Associated with PGM1-congenital disorder of glycosylation.

What condition is associated with PGM1 p.Arg405Ser (c.1213C>A)?

PGM1 p.Arg405Ser (c.1213C>A) is associated with PGM1-congenital disorder of glycosylation (ClinVar).

How common is PGM1 p.Arg405Ser (c.1213C>A) in the general population?

PGM1 p.Arg405Ser (c.1213C>A) is ultra-rare (popmax 0.0681%, sas) (gnomAD).

How is PGM1-CDG inherited?

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

What do computational predictors say about PGM1 p.Arg405Ser (c.1213C>A)?

AlphaMissense predicts likely pathogenic (score 0.7508) — an in-silico prediction, not a clinical call.

PGM1 p.Arg405Ser

c.1213C>A · rs754131603 · VCV1023761

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7508 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0681%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

PGM1-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.7508	likely pathogenic
REVEL	0.31	indeterminate
SaProt	LLR -7.09	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 23 kb · p 0.87 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0681% South Asian · 62/91,082 alleles

Filtering AF 0.0544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0495%

Overall 0.00428% 69/1,613,936 alleles · ultra-rare exomes 67/1,461,786 · genomes 2/152,150 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0681%	1,469
Remaining individualsnot grpmax-eligible	0.0048%	20,826
European (non-Finnish)	0.000339%	294,993

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: PGM1
Protein: p.Arg405Ser
Coding: c.1213C>A
MANE Select: NM_002633
dbSNP: rs754131603
Type: single nucleotide variant
Location: chr1:63648585 (GRCh38)
Gene constraint: LOEUF 1.189 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 97.27 · 16 PDB
Residue 405: an α-helix

Full PGM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PGM1-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For PGM1-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

PGM1 p.Arg405His Uncertain significance ★ ⚠ same residue
PGM1 p.Arg217Ter Pathogenic ★★ same condition
PGM1 p.Arg293Ter Pathogenic/Likely pathogenic ★★ same condition
PGM1 p.Arg499Ter Pathogenic/Likely pathogenic ★★ same condition
PGM1 p.Arg503Ter Pathogenic ★★ same condition
PGM1 p.Arg515Gln Pathogenic/Likely pathogenic ★★ same condition
PGM1 p.Asp263Tyr Pathogenic/Likely pathogenic ★★ same condition
PGM1 p.Gly291Arg 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/pgm1-p-arg405ser (accessed [today's date]).

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