Is ELANE p.Ala69fs (c.205del) pathogenic?

ELANE p.Ala69fs (c.205del) is classified Uncertain significance in ELANE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-19). Very rare (popmax 0.000382%); Associated with cyclic neutropenia.

What condition is associated with ELANE p.Ala69fs (c.205del)?

ELANE p.Ala69fs (c.205del) is associated with cyclic neutropenia, neutropenia, severe congenital, 1, autosomal dominant (ClinVar).

How common is ELANE p.Ala69fs (c.205del) in the general population?

ELANE p.Ala69fs (c.205del) is very rare (popmax 0.000382%) (gnomAD).

How is Cyclic neutropenia inherited?

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

ELANE p.Ala69fs

c.205del · rs1195157089 · VCV2078397

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000382%)

Conditions

cyclic neutropenia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 5
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -9.8	GERP -4.7
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000382%

Overall 0.000382% 6/1,569,194 alleles · very rare

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: ELANE
Protein: p.Ala69fs
Coding: c.205del
MANE Select: NM_001972
dbSNP: rs1195157089
Type: Deletion
Location: chr19:853013 (GRCh38)
Gene constraint: LOEUF 1.245 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.42 · 38 PDB
Residue 69: a disulfide bond; an α-helix; the peptidase s1 domain; a UniProt-annotated variant site (in scn1)

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

Disease context

cyclic neutropenia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neutropenia, severe congenital, 1, autosomal dominant

For Cyclic neutropenia (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

ELANE p.Ala69_Asn74del Likely pathogenic same residue
ELANE p.Ala69Thr Uncertain significance ★★ ⚠ same residue
ELANE p.Pro111_Val112insTer Uncertain significance ★★ same condition
ELANE c.597+5del Pathogenic ★ same condition
ELANE p.Ala195fs Likely pathogenic ★ same condition
ELANE p.Asp201fs Likely pathogenic ★ same condition
ELANE p.Asp230fs Pathogenic ★ same condition
ELANE p.Gly192fs Pathogenic ★ 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/elane-p-ala69fs (accessed [today's date]).

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