Is ELANE p.Val190Met (c.568G>A) pathogenic?

ELANE p.Val190Met (c.568G>A) is classified Conflicting classifications of pathogenicity in ELANE (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-01). AlphaMissense: likely pathogenic (0.5698); Very rare (popmax 0.00483%, nfe); Associated with cyclic neutropenia.

What condition is associated with ELANE p.Val190Met (c.568G>A)?

ELANE p.Val190Met (c.568G>A) is associated with cyclic neutropenia, autoinflammatory syndrome, neutropenia, severe congenital, 1, autosomal dominant (ClinVar).

How common is ELANE p.Val190Met (c.568G>A) in the general population?

ELANE p.Val190Met (c.568G>A) is very rare (popmax 0.00483%, 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.Val190Met (c.568G>A)?

AlphaMissense predicts likely pathogenic (score 0.5698) — an in-silico prediction, not a clinical call.

ELANE p.Val190Met

c.568G>A · rs367663236 · VCV242296

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.5698 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00483%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cyclic neutropenia

Computational evidence

Protein change
AlphaMissense	0.5698	likely pathogenic
REVEL	0.523	indeterminate
SaProt	LLR -9.60	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.47	donor loss · deltas
Constraint at this position
Conservation	phyloP 9.5	GERP 2.1, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,171 bp · p 0.52 · regional, not allelic
Overall
CADD	23.9	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 0.00483% European (non-Finnish) · 57/1,179,952 alleles

Filtering AF 0.00378% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.00392% 63/1,609,064 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00483%	20,701
Remaining individualsnot grpmax-eligible	0.00481%	20,780
African / African-American	0.00267%	37,452
East Asian	0.00223%	44,894

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.Val190Met
Coding: c.568G>A
MANE Select: NM_001972
dbSNP: rs367663236
Type: single nucleotide variant
Location: chr19:855765 (GRCh38)
Gene constraint: LOEUF 1.245 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.42 · 38 PDB
Residue 190: a disulfide bond; the peptidase s1 domain; a UniProt-annotated variant site (in scn1 and ch)

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: autoinflammatory syndrome 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.Val190= Likely pathogenic ★★ same residue
ELANE p.Val190Gly Uncertain significance ★★ ⚠ same residue
ELANE p.Val190Leu Uncertain significance ★ ⚠ same residue
ELANE p.Val190fs 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

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-val190met (accessed [today's date]).

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