Is GFI1 p.Arg3Pro (c.8G>C) pathogenic?

GFI1 p.Arg3Pro (c.8G>C) is classified Uncertain significance in GFI1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-17). AlphaMissense: ambiguous (0.3554); Absent from gnomAD v4.1; Associated with neutropenia, severe congenital, 2, autosomal dominant.

What condition is associated with GFI1 p.Arg3Pro (c.8G>C)?

GFI1 p.Arg3Pro (c.8G>C) is associated with neutropenia, severe congenital, 2, autosomal dominant (ClinVar).

How common is GFI1 p.Arg3Pro (c.8G>C) in the general population?

GFI1 p.Arg3Pro (c.8G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GFI1 p.Arg3Pro (c.8G>C)?

AlphaMissense predicts ambiguous (score 0.3554) — an in-silico prediction, not a clinical call.

GFI1 p.Arg3Pro

Q: How is Autosomal dominant severe congenital neutropenia inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.8G>C · VCV4811679

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3554 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

neutropenia, severe congenital, 2, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.3554	ambiguous
REVEL	0.405	indeterminate
SaProt	LLR -14.80	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,697 bp · p 0.96 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GFI1
Protein: p.Arg3Pro
Coding: c.8G>C
MANE Select: NM_005263
Type: single nucleotide variant
Location: chr1:92483480 (GRCh38)
Gene constraint: LOEUF 0.715 · pLI 0.05 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 58.33
Residue 3: the 'disordered' region; the 'snag domain' region

Full GFI1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neutropenia, severe congenital, 2, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant severe congenital neutropenia (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

GFI1 p.Arg3= Likely benign ★ same residue
GFI1 p.Asn382Ser Pathogenic ★★ ⚠ same condition
GFI1 p.Ala128Glu Uncertain significance ★★ ⚠ same condition
GFI1 p.Ala128Gly Uncertain significance ★★ ⚠ same condition
GFI1 p.Ala144Gly Uncertain significance ★★ ⚠ same condition
GFI1 p.Ala158Ser Uncertain significance ★★ ⚠ same condition
GFI1 p.Ala165Asp Uncertain significance ★★ ⚠ same condition
GFI1 p.Ala174Val Uncertain significance ★★ ⚠ 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/gfi1-p-arg3pro (accessed [today's date]).

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