Is G6PC3 p.Pro44= (c.132C>T) pathogenic?

G6PC3 p.Pro44= (c.132C>T) is classified Likely benign in G6PC3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-03). Very rare (popmax 0.01%, amr); Associated with autosomal recessive severe congenital neutropenia due to G6PC3 deficiency.

What condition is associated with G6PC3 p.Pro44= (c.132C>T)?

G6PC3 p.Pro44= (c.132C>T) is associated with autosomal recessive severe congenital neutropenia due to G6PC3 deficiency (ClinVar).

How common is G6PC3 p.Pro44= (c.132C>T) in the general population?

G6PC3 p.Pro44= (c.132C>T) is very rare (popmax 0.01%, amr) (gnomAD).

G6PC3 p.Pro44=

Q: How is Severe congenital neutropenia due to G6PC3 deficiency inherited?

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

c.132C>T · rs200427598 · VCV1114437

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Conditions

autosomal recessive severe congenital neutropenia due to G6PC3 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.11	GERP -3.9, phastCons 0.51
Overall
CADD	12.58	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/60,004 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000496% 8/1,613,876 alleles · very rare exomes 6/1,461,542 · genomes 2/152,334 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,001
Remaining individualsnot grpmax-eligible	0.0016%	62,494
African / African-American	0.00133%	75,054

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: G6PC3
Protein: p.Pro44=
Coding: c.132C>T
MANE Select: NM_138387
dbSNP: rs200427598
Type: single nucleotide variant
Location: chr17:44071097 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.79
Residue 44: a UniProt-annotated variant site (in scn4; complete loss of activity); a UniProt-annotated variant site (in scn4; complete loss of activity; purified neutrophils from patients have higher levels of spontaneous and staurosporine-induced apoptosis than controls)

Full G6PC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive severe congenital neutropenia due to G6PC3 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe congenital neutropenia due to G6PC3 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

G6PC3 p.Pro44Leu Pathogenic/Likely pathogenic ★★ same residue
G6PC3 p.Pro44Ser Pathogenic ★★ same residue
G6PC3 p.Arg161Gln Pathogenic/Likely pathogenic ★★ same condition
G6PC3 p.Arg161Ter Pathogenic ★★ same condition
G6PC3 p.Arg189Ter Pathogenic ★★ same condition
G6PC3 p.Arg253His Pathogenic ★★ same condition
G6PC3 p.Gln277Ter Pathogenic ★★ same condition
G6PC3 p.Gly109Ser 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/g6pc3-p-pro44 (accessed [today's date]).

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