Is GFI1 p.Leu135Pro (c.404T>C) pathogenic?

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.

What condition is associated with GFI1 p.Leu135Pro (c.404T>C)?

GFI1 p.Leu135Pro (c.404T>C) is associated with neutropenia, severe congenital, 2, autosomal dominant (ClinVar).

How common is GFI1 p.Leu135Pro (c.404T>C) in the general population?

GFI1 p.Leu135Pro (c.404T>C) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about GFI1 p.Leu135Pro (c.404T>C)?

AlphaMissense predicts likely pathogenic (score 0.6746) — an in-silico prediction, not a clinical call.

GFI1 p.Leu135Pro

Q: How is Autosomal dominant severe congenital neutropenia inherited?

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

c.404T>C · VCV3853739

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6746 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

neutropenia, severe congenital, 2, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.6746	likely pathogenic
REVEL	0.359	indeterminate
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.3, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,697 bp · p 0.96 · regional, not allelic
Overall
CADD	26.4	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 0.00111% South Asian · 1/89,886 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000249% 4/1,606,118 alleles · very rare exomes 4/1,453,820 · genomes 0/152,298 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00111%	89,886
European (non-Finnish)	0.000255%	392,326

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.Leu135Pro
Coding: c.404T>C
MANE Select: NM_005263
Type: single nucleotide variant
Location: chr1:92480983 (GRCh38)
Gene constraint: LOEUF 0.715 · pLI 0.05 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 58.33

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.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
GFI1 p.Ala179Thr 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-leu135pro (accessed [today's date]).

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