Is ELANE p.Ala127Val (c.380C>T) pathogenic?

ELANE p.Ala127Val (c.380C>T) is classified Likely benign in ELANE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-06). AlphaMissense: ambiguous (0.373); Ultra-rare (popmax 0.0934%, amr); Associated with cyclic neutropenia.

What condition is associated with ELANE p.Ala127Val (c.380C>T)?

ELANE p.Ala127Val (c.380C>T) is associated with cyclic neutropenia, neutropenia, severe congenital, 1, autosomal dominant (ClinVar).

How common is ELANE p.Ala127Val (c.380C>T) in the general population?

ELANE p.Ala127Val (c.380C>T) is ultra-rare (popmax 0.0934%, amr) (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.Ala127Val (c.380C>T)?

AlphaMissense predicts ambiguous (score 0.373) — an in-silico prediction, not a clinical call.

ELANE p.Ala127Val

c.380C>T · rs781705775 · VCV702340

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.373 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0934%, amr)

Conditions

cyclic neutropenia

Computational evidence

Protein change
AlphaMissense	0.373	ambiguous
REVEL	0.413	indeterminate
SaProt	LLR -10.48	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,171 bp · p 0.52 · regional, not allelic
Overall
CADD	22.0	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 0.0934% Admixed American · 56/59,964 alleles

Filtering AF 0.0738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0667%

Overall 0.0035% 56/1,599,586 alleles · ultra-rare exomes 50/1,447,372 · genomes 6/152,214 · 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.Ala127Val
Coding: c.380C>T
MANE Select: NM_001972
dbSNP: rs781705775
Type: single nucleotide variant
Location: chr19:855577 (GRCh38)
Gene constraint: LOEUF 1.245 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.42 · 38 PDB
Residue 127: 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.Ala127Asp Pathogenic same residue
ELANE p.Ala127Gly Uncertain significance ★ same residue
ELANE p.Ala127Thr 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-ala127val (accessed [today's date]).

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