Is G6PC3 p.Pro247Arg (c.740C>G) pathogenic?

G6PC3 p.Pro247Arg (c.740C>G) is classified Uncertain significance in G6PC3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-26). AlphaMissense: likely pathogenic (0.8826); Very rare (popmax 0.000847%, nfe); Associated with Inborn genetic diseases.

What condition is associated with G6PC3 p.Pro247Arg (c.740C>G)?

G6PC3 p.Pro247Arg (c.740C>G) is associated with Inborn genetic diseases, autosomal recessive severe congenital neutropenia due to G6PC3 deficiency (ClinVar).

How common is G6PC3 p.Pro247Arg (c.740C>G) in the general population?

G6PC3 p.Pro247Arg (c.740C>G) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about G6PC3 p.Pro247Arg (c.740C>G)?

AlphaMissense predicts likely pathogenic (score 0.8826) — an in-silico prediction, not a clinical call.

G6PC3 p.Pro247Arg

c.740C>G · rs1158728815 · VCV1379204

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8826 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8826	likely pathogenic
REVEL	0.797	moderately pathogenic-leaning
SaProt	LLR -15.16	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 5,074 bp · p 0.0017 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000847% European (non-Finnish) · 10/1,180,028 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00062% 10/1,612,798 alleles · very rare exomes 10/1,460,512 · genomes 0/152,286 · joint denominator

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.Pro247Arg
Coding: c.740C>G
MANE Select: NM_138387
dbSNP: rs1158728815
Type: single nucleotide variant
Location: chr17:44075742 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.79

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive severe congenital neutropenia due to G6PC3 deficiency

Similar variants

G6PC3 p.Pro247Ser Uncertain significance ★ ⚠ 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
G6PC3 p.Gly260Arg 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-pro247arg (accessed [today's date]).

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