Is G6PC3 p.Leu129Pro (c.386T>C) pathogenic?

G6PC3 p.Leu129Pro (c.386T>C) is classified Uncertain significance in G6PC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-03). AlphaMissense: ambiguous (0.5235); Very rare (popmax 0.00133%, afr); Associated with autosomal recessive severe congenital neutropenia due to G6PC3 deficiency.

What condition is associated with G6PC3 p.Leu129Pro (c.386T>C)?

G6PC3 p.Leu129Pro (c.386T>C) is associated with autosomal recessive severe congenital neutropenia due to G6PC3 deficiency (ClinVar).

How common is G6PC3 p.Leu129Pro (c.386T>C) in the general population?

G6PC3 p.Leu129Pro (c.386T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about G6PC3 p.Leu129Pro (c.386T>C)?

AlphaMissense predicts ambiguous (score 0.5235) — an in-silico prediction, not a clinical call.

G6PC3 p.Leu129Pro

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.386T>C · rs1280283104 · VCV2105901

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5235 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

autosomal recessive severe congenital neutropenia due to G6PC3 deficiency

Computational evidence

Protein change
AlphaMissense	0.5235	ambiguous
REVEL	0.543	indeterminate
SaProt	LLR -13.31	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2.3, phastCons 0.98
Regional constraint	o/e 0.85	unconstrained · MANE · 5,074 bp · p 0.0017 · regional, not allelic
Overall
CADD	25.1	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 0.00133% African / African-American · 1/74,942 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00105% 17/1,613,932 alleles · very rare exomes 16/1,461,722 · genomes 1/152,210 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,482
African / African-Americangrpmax	0.00133%	74,942
European (non-Finnish)	0.00127%	78,666

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu129Pro
Coding: c.386T>C
MANE Select: NM_138387
dbSNP: rs1280283104
Type: single nucleotide variant
Location: chr17:44074740 (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

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.Leu129Arg Uncertain significance ★ same residue
G6PC3 p.Leu129Val 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

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-leu129pro (accessed [today's date]).

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