Is ELANE p.Ala8Val (c.23C>T) pathogenic?

ELANE p.Ala8Val (c.23C>T) is classified Conflicting classifications of pathogenicity in ELANE (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-21). AlphaMissense: likely benign (0.1186); Ultra-rare (popmax 0.0454%, afr); Associated with neutropenia, severe congenital, 1, autosomal dominant.

What condition is associated with ELANE p.Ala8Val (c.23C>T)?

ELANE p.Ala8Val (c.23C>T) is associated with neutropenia, severe congenital, 1, autosomal dominant, cyclic neutropenia (ClinVar).

How common is ELANE p.Ala8Val (c.23C>T) in the general population?

ELANE p.Ala8Val (c.23C>T) is ultra-rare (popmax 0.0454%, afr) (gnomAD).

What do computational predictors say about ELANE p.Ala8Val (c.23C>T)?

AlphaMissense predicts likely benign (score 0.1186) — an in-silico prediction, not a clinical call.

ELANE p.Ala8Val

Q: How is Autosomal dominant severe congenital neutropenia inherited?

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

c.23C>T · rs201961347 · VCV242276

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1186 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0454%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neutropenia, severe congenital, 1, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.1186	likely benign
REVEL	0.162	moderately benign-leaning
SaProt	LLR -6.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.33	GERP -1.9
Regional constraint	o/e 1.02	unconstrained · MANE · 597 bp · p 0.86 · regional, not allelic
Overall
CADD	6.484	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 0.0454% African / African-American · 34/74,932 alleles

Filtering AF 0.0334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0292%

Overall 0.00261% 42/1,610,998 alleles · ultra-rare exomes 30/1,458,822 · genomes 12/152,176 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0454%	2,204
Remaining individualsnot grpmax-eligible	0.00641%	15,606
Admixed American	0.00167%	59,994
European (non-Finnish)	0.000254%	393,307

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.Ala8Val
Coding: c.23C>T
MANE Select: NM_001972
dbSNP: rs201961347
Type: single nucleotide variant
Location: chr19:852351 (GRCh38)
Gene constraint: LOEUF 1.245 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.42 · 38 PDB

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.Ala8Pro Uncertain significance ★★ ⚠ same residue
ELANE p.Ala8= Likely benign ★★ same residue
ELANE p.Ala8Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
ELANE p.Ala8Thr Conflicting classifications of pathogenicity ★ ⚠ 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-ala8val (accessed [today's date]).

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