Is G6PC3 p.Pro44Ser (c.130C>T) pathogenic?

G6PC3 p.Pro44Ser (c.130C>T) is classified Pathogenic in G6PC3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-04-28). AlphaMissense: likely pathogenic (0.6653); Ultra-rare (popmax 0.0264%, sas); Associated with autosomal recessive severe congenital neutropenia due to G6PC3 deficiency.

What condition is associated with G6PC3 p.Pro44Ser (c.130C>T)?

G6PC3 p.Pro44Ser (c.130C>T) is associated with autosomal recessive severe congenital neutropenia due to G6PC3 deficiency (ClinVar).

How common is G6PC3 p.Pro44Ser (c.130C>T) in the general population?

G6PC3 p.Pro44Ser (c.130C>T) is ultra-rare (popmax 0.0264%, sas) (gnomAD).

What do computational predictors say about G6PC3 p.Pro44Ser (c.130C>T)?

AlphaMissense predicts likely pathogenic (score 0.6653) — an in-silico prediction, not a clinical call.

G6PC3 p.Pro44Ser

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.130C>T · rs775224457 · VCV189781

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.6653 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0264%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive severe congenital neutropenia due to G6PC3 deficiency

Computational evidence

Protein change
AlphaMissense	0.6653	likely pathogenic ✓ concordant with ClinVar
REVEL	0.719	pathogenic-leaning
SaProt	LLR -11.94	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 5,074 bp · p 0.0017 · regional, not allelic
Overall
CADD	28.0	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 0.0264% South Asian · 24/90,950 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.00173% 28/1,613,854 alleles · ultra-rare exomes 28/1,461,514 · genomes 0/152,340 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0264%	3,790
European (non-Finnish)	0.000339%	294,979

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.Pro44Ser
Coding: c.130C>T
MANE Select: NM_138387
dbSNP: rs775224457
Type: single nucleotide variant
Location: chr17:44071095 (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.Pro44= Likely benign ★★ 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-pro44ser (accessed [today's date]).

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