# NM_005263.5(GFI1):c.404T>C (p.Leu135Pro)

https://sugi.bio/variant/gfi1-p-leu135pro

## Summary

**GFI1 p.Leu135Pro (c.404T>C)** is classified **Uncertain significance** in GFI1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-03). AlphaMissense: likely pathogenic (0.6746); Very rare (popmax 0.00111%, sas); Associated with neutropenia, severe congenital, 2, autosomal dominant.

**At a glance:** Uncertain significance · review: Multiple submitters · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00111%, sas)

## For patients & families {#patients}

This is a change in the GFI1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to neutropenia, severe congenital, 2, autosomal dominant.

*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 dominant |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | <1 / 1 000 000 (Europe) |
| Diagnostic panels | GFI1 is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Autosomal dominant severe congenital neutropenia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Decreased total neutrophil count — Obligate (100%)
- Recurrent bacterial infections — Very frequent (99-80%)
- Recurrent viral infections — Very frequent (99-80%)
- Oral ulcer — Frequent (79-30%)
- Gingivitis — Frequent (79-30%)
- Periodontitis — Frequent (79-30%)
- Recurrent skin infections — Frequent (79-30%)
- Lymphopenia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015616/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GFI1](https://sugi.bio/atlas/gene/GFI1/) |
| Protein change (HGVS p.) | p.Leu135Pro |
| Coding change (HGVS c.) | c.404T>C |
| MANE Select transcript | [NM_005263](https://www.ncbi.nlm.nih.gov/nuccore/NM_005263) |
| Variant type | single nucleotide variant |
| Location | chr1:92480983-92480983 (GRCh38) |
| ClinVar | [VCV3853739](https://www.ncbi.nlm.nih.gov/clinvar/variation/3853739/) |

**All HGVS expressions:** `LRG_63:g.10894T>C`, `LRG_63t1:c.404T>C`, `NC_000001.10:g.92946540A>G`, `NC_000001.11:g.92480983A>G`, `NG_007874.1:g.10894T>C`, `NM_001127215.3:c.404T>C`, `NM_001127216.3:c.404T>C`, `NM_005263.5:c.404T>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.6746)
- REVEL 0.359 (indeterminate)
- SaProt LLR -6.824 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate
- Conservation: phyloP 10.895, GERP 1.27, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.4**. 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 1.00** across the covering region of the MANE Select transcript (92,480,790–92,483,487), spanning 2,697 bp. Chi-square p 0.96. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for GFI1 (501 scored positions, the nearest 106 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.00111%** (sas) · FAF95 6.8e-05% · FAF99 1.9e-05% · 1/89,886 in the highest group · 4/1,606,118 alleles overall — very rare (popmax 0.00111%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00111% | 89,886 |
| European (non-Finnish) | 0.000255% | 392,326 |

*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}

**GFI1** population constraint: LOEUF 0.715, pLI 0.048531, missense-Z 0.70931; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 58.33, 29% of residues very-high.

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

*Describes the biological roles of GFI1 (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:** GFI1's established molecular role includes transcription cis-regulatory region binding.


### Pathways affected {#pathways}

GFI1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Transcriptional regulation of granulopoiesis](https://reactome.org/content/detail/R-HSA-9616222) | other |

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

**Molecular function:** transcription cis-regulatory region binding, DNA-binding transcription repressor activity, RNA polymerase II-specific, enzyme-substrate adaptor activity, sequence-specific double-stranded DNA binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, DNA damage response, negative regulation of vitamin D biosynthetic process, negative regulation of neuron projection development, regulation of toll-like receptor signaling pathway, negative regulation of DNA-templated transcription.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-03.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-03 |

## Associated conditions {#conditions}

[neutropenia, severe congenital, 2, autosomal dominant](https://sugi.bio/atlas/disease/neutropenia-severe-congenital-2-autosomal-dominant/).

**Reported phenotype names (ClinVar):** Neutropenia, severe congenital, 2, autosomal dominant, not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related GFI1 variant pages (same residue, condition, or type): [GFI1 p.Asn382Ser](/variant/gfi1-p-asn382ser), [GFI1 p.Ala128Glu](/variant/gfi1-p-ala128glu), [GFI1 p.Ala128Gly](/variant/gfi1-p-ala128gly), [GFI1 p.Ala144Gly](/variant/gfi1-p-ala144gly), [GFI1 p.Ala158Ser](/variant/gfi1-p-ala158ser), [GFI1 p.Ala165Asp](/variant/gfi1-p-ala165asp), [GFI1 p.Ala174Val](/variant/gfi1-p-ala174val), [GFI1 p.Ala179Thr](/variant/gfi1-p-ala179thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 3853739). 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.*