Is ELANE p.Arg220Pro (c.659G>C) pathogenic?

ELANE p.Arg220Pro (c.659G>C) is classified Conflicting classifications of pathogenicity in ELANE (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2019-10-29). AlphaMissense: ambiguous (0.5591); Very rare (popmax 0.000678%, nfe); Associated with cyclic neutropenia.

What condition is associated with ELANE p.Arg220Pro (c.659G>C)?

ELANE p.Arg220Pro (c.659G>C) is associated with cyclic neutropenia, neutropenia, severe congenital, 1, autosomal dominant (ClinVar).

How common is ELANE p.Arg220Pro (c.659G>C) in the general population?

ELANE p.Arg220Pro (c.659G>C) is very rare (popmax 0.000678%, nfe) (gnomAD).

How is Cyclic neutropenia inherited?

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

What do computational predictors say about ELANE p.Arg220Pro (c.659G>C)?

AlphaMissense predicts ambiguous (score 0.5591) — an in-silico prediction, not a clinical call.

ELANE p.Arg220Pro

c.659G>C · rs137854445 · VCV851966

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5591 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Conditions

cyclic neutropenia

Computational evidence

Protein change
AlphaMissense	0.5591	ambiguous
REVEL	0.607	indeterminate
SaProt	LLR -8.51	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.50 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.7	GERP -0.16, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,171 bp · p 0.52 · regional, not allelic
Overall
CADD	18.63	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 0.000678% European (non-Finnish) · 8/1,180,036 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,613,402 alleles · very rare exomes 7/1,461,204 · genomes 1/152,198 · joint denominator

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.Arg220Pro
Coding: c.659G>C
MANE Select: NM_001972
dbSNP: rs137854445
Type: single nucleotide variant
Location: chr19:856019 (GRCh38)
Gene constraint: LOEUF 1.245 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.42 · 38 PDB
Residue 220: a UniProt-annotated variant site (in ch and scn1; loss of interaction with notch2nl and loss of notch2nl and notch2 proteolytic cleavage); a β-strand; the peptidase s1 domain

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.Arg220Gln Pathogenic/Likely pathogenic ★★ ⚠ same residue
ELANE p.Arg220Trp Likely pathogenic ★ ⚠ same residue
ELANE p.Arg220Gly Uncertain significance ★ same residue
ELANE c.597+1G>A Pathogenic ★★ same condition
ELANE c.597+1G>C Pathogenic ★★ same condition
ELANE c.597+1G>T Pathogenic ★★ same condition
ELANE c.597+5G>A Pathogenic/Likely pathogenic ★★ same condition
ELANE p.Ala57Thr Pathogenic/Likely 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-arg220pro (accessed [today's date]).

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