Is ELANE p.Val45Met (c.133G>A) pathogenic?

ELANE p.Val45Met (c.133G>A) is classified Uncertain significance in ELANE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-12). AlphaMissense: likely pathogenic (0.8934); Absent from gnomAD v4.1; Associated with neutropenia, severe congenital, 1, autosomal dominant.

What condition is associated with ELANE p.Val45Met (c.133G>A)?

ELANE p.Val45Met (c.133G>A) is associated with neutropenia, severe congenital, 1, autosomal dominant, cyclic neutropenia (ClinVar).

How common is ELANE p.Val45Met (c.133G>A) in the general population?

ELANE p.Val45Met (c.133G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ELANE p.Val45Met (c.133G>A)?

AlphaMissense predicts likely pathogenic (score 0.8934) — an in-silico prediction, not a clinical call.

ELANE p.Val45Met

Q: How is Autosomal dominant severe congenital neutropenia inherited?

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

c.133G>A · rs1599290793 · VCV2925629

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8934 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neutropenia, severe congenital, 1, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.8934	likely pathogenic
REVEL	0.69	pathogenic-leaning
SaProt	LLR -12.53	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 62 bp · p 0.00023 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ELANE
Protein: p.Val45Met
Coding: c.133G>A
MANE Select: NM_001972
dbSNP: rs1599290793
Type: single nucleotide variant
Location: chr19:852941 (GRCh38)
Gene constraint: LOEUF 1.245 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.42 · 38 PDB
Residue 45: a β-strand; a UniProt-annotated variant site (in scn1); a UniProt-annotated variant site (in ch); the peptidase s1 domain

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

Disease context

neutropenia, severe congenital, 1, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cyclic neutropenia

For Autosomal dominant severe congenital neutropenia (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

ELANE p.Val45Gly Uncertain significance ★ ⚠ same residue
ELANE p.Val45= Likely benign ★ same residue
ELANE p.Val45Leu Likely pathogenic ★ same residue
ELANE p.Val45Ala Likely benign ★ 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-val45met (accessed [today's date]).

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