Is GFI1 p.Pro57Ser (c.169C>T) pathogenic?

GFI1 p.Pro57Ser (c.169C>T) is classified Uncertain significance in GFI1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-24). AlphaMissense: likely benign (0.0832); Ultra-rare (popmax 0.0671%, mid); Associated with neutropenia, severe congenital, 2, autosomal dominant.

What condition is associated with GFI1 p.Pro57Ser (c.169C>T)?

GFI1 p.Pro57Ser (c.169C>T) is associated with neutropenia, severe congenital, 2, autosomal dominant (ClinVar).

How common is GFI1 p.Pro57Ser (c.169C>T) in the general population?

GFI1 p.Pro57Ser (c.169C>T) is ultra-rare (popmax 0.0671%, mid) (gnomAD).

What do computational predictors say about GFI1 p.Pro57Ser (c.169C>T)?

AlphaMissense predicts likely benign (score 0.0832) — an in-silico prediction, not a clinical call.

GFI1 p.Pro57Ser

Q: How is Autosomal dominant severe congenital neutropenia inherited?

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

c.169C>T · rs1024012420 · VCV2417274

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0832 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0671%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neutropenia, severe congenital, 2, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.0832	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -6.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,697 bp · p 0.96 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0671% Middle Eastern · 4/5,960 alleles

Filtering AF 0.0229% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.00149% 24/1,610,146 alleles · ultra-rare exomes 20/1,457,816 · genomes 4/152,330 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0671%	1,490
African / African-American	0.0147%	6,811
East Asian	0.00223%	44,786
Remaining individualsnot grpmax-eligible	0.0016%	62,318
European (non-Finnish)	0.000594%	168,258

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: GFI1
Protein: p.Pro57Ser
Coding: c.169C>T
MANE Select: NM_005263
dbSNP: rs1024012420
Type: single nucleotide variant
Location: chr1:92482993 (GRCh38)
Gene constraint: LOEUF 0.715 · pLI 0.05 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 58.33
Residue 57: the 'disordered' 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.Pro57Leu Uncertain significance ★★ ⚠ same residue
GFI1 p.Pro57= Likely benign ★ same residue
GFI1 p.Pro57Arg Uncertain significance ★ ⚠ 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

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-pro57ser (accessed [today's date]).

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