# NM_138387.4(G6PC3):c.130C>T (p.Pro44Ser)

https://sugi.bio/variant/g6pc3-p-pro44ser

## Summary

**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.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs775224457 · 5 submitters · 1 linked condition · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0264%, sas)

## For patients & families {#patients}

This is a change in the G6PC3 gene that is considered disease-causing, submitted by 5 submitters, and is linked to autosomal recessive severe congenital neutropenia due to G6PC3 deficiency.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | G6PC3 is a diagnostic-grade gene on 14 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017511/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [G6PC3](https://sugi.bio/atlas/gene/G6PC3/) |
| Protein change (HGVS p.) | p.Pro44Ser |
| Coding change (HGVS c.) | c.130C>T |
| MANE Select transcript | [NM_138387](https://www.ncbi.nlm.nih.gov/nuccore/NM_138387) |
| dbSNP | [rs775224457](https://www.ncbi.nlm.nih.gov/snp/rs775224457/) |
| Variant type | single nucleotide variant |
| Location | chr17:44071095-44071095 (GRCh38) |
| ClinVar | [VCV189781](https://www.ncbi.nlm.nih.gov/clinvar/variation/189781/) |

**All HGVS expressions:** `LRG_182:g.5366C>T`, `LRG_182t1:c.130C>T`, `NC_000017.10:g.42148463C>T`, `NC_000017.11:g.44071095C>T`, `NG_015818.1:g.5366C>T`, `NM_001319945.2:c.130C>T`, `NM_001384165.1:c.-275C>T`, `NM_001384166.1:c.-410C>T`, `NM_001384167.1:c.-400C>T`, `NM_001384168.1:c.-312+381C>T`, `NM_138387.4:c.130C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.6653) — concordant with the pathogenic call
- REVEL 0.719 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.936 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.634, GERP 2.26, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.85** across the covering region of the MANE Select transcript (44,070,966–44,076,040), spanning 5,074 bp. Chi-square p 0.0017. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0264%** (sas) · FAF95 0.0181% · FAF99 0.0154% · 24/90,950 in the highest group · 28/1,613,854 alleles overall — ultra-rare (popmax 0.0264%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0264% | 3,790 |
| European (non-Finnish) | 0.000339% | 294,979 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**G6PC3** population constraint: LOEUF 1.008, pLI 5.3335e-08, missense-Z 1.2972; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **autosomal recessive severe congenital neutropenia due to G6PC3 deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **44** lies in 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).

AlphaFold model confidence (whole protein): pLDDT 92.79, 84% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of G6PC3 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** G6PC3's established molecular role includes glucose-6-phosphatase activity. In Reactome, G6PC3 is annotated in disease pathway(s) including **Severe congenital neutropenia type 4 (G6PC3)**.

**Disease mechanism (Reactome):** G6PC3 loss or alteration is curated in [Severe congenital neutropenia type 4 (G6PC3)](https://reactome.org/content/detail/R-HSA-3282872).

### Pathways affected {#pathways}

G6PC3 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Severe congenital neutropenia type 4 (G6PC3)](https://reactome.org/content/detail/R-HSA-3282872) | curated |
| [Gluconeogenesis](https://reactome.org/content/detail/R-HSA-70263) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** glucose-6-phosphatase activity.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-04-28.

**Submitter consensus:** conflicting (4 Pathogenic, 1 not provided).

**Submission history:** 5 submissions (2016–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Pathogenic | criteria provided, single submitter | clinical testing | 2016-05-03 |
| GeneReviews | not provided | no classification provided | literature only |  |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-05 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2020-12-01 |

## Associated conditions {#conditions}

[autosomal recessive severe congenital neutropenia due to G6PC3 deficiency](https://sugi.bio/atlas/disease/autosomal-recessive-severe-congenital-neutropenia-due-to-g6pc3-deficiency/).

**Reported phenotype names (ClinVar):** Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency, not provided, none provided, NEUTROPENIA, SEVERE CONGENITAL, 4, AUTOSOMAL RECESSIVE, G6PC3 Deficiency.

## Same-residue context {#hotspot}

Residue **44** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [G6PC3 p.Pro44Leu](/variant/g6pc3-p-pro44leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related G6PC3 variant pages (same residue, condition, or type): [G6PC3 p.Pro44Leu](/variant/g6pc3-p-pro44leu), [G6PC3 p.Pro44=](/variant/g6pc3-p-pro44), [G6PC3 p.Arg161Gln](/variant/g6pc3-p-arg161gln), [G6PC3 p.Arg161Ter](/variant/g6pc3-p-arg161ter), [G6PC3 p.Arg189Ter](/variant/g6pc3-p-arg189ter), [G6PC3 p.Arg253His](/variant/g6pc3-p-arg253his), [G6PC3 p.Gln277Ter](/variant/g6pc3-p-gln277ter), [G6PC3 p.Gly109Ser](/variant/g6pc3-p-gly109ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 189781). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*