Is ELANE p.Ala166Thr (c.496G>A) pathogenic?

ELANE p.Ala166Thr (c.496G>A) is classified Conflicting classifications of pathogenicity in ELANE (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-27). AlphaMissense: likely benign (0.263); Ultra-rare (popmax 0.0167%, mid); Associated with neutropenia, severe congenital, 1, autosomal dominant.

What condition is associated with ELANE p.Ala166Thr (c.496G>A)?

ELANE p.Ala166Thr (c.496G>A) is associated with neutropenia, severe congenital, 1, autosomal dominant, cyclic neutropenia (ClinVar).

How common is ELANE p.Ala166Thr (c.496G>A) in the general population?

ELANE p.Ala166Thr (c.496G>A) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about ELANE p.Ala166Thr (c.496G>A)?

AlphaMissense predicts likely benign (score 0.263) — an in-silico prediction, not a clinical call.

ELANE p.Ala166Thr

Q: How is Autosomal dominant severe congenital neutropenia inherited?

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

c.496G>A · rs201788817 · VCV2422038

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.263 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neutropenia, severe congenital, 1, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.263	likely benign
REVEL	0.473	indeterminate
SaProt	LLR -7.05	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.73	GERP -4.1, phastCons 0.05
Regional constraint	o/e 1.04	unconstrained · MANE · 3,171 bp · p 0.52 · regional, not allelic
Overall
CADD	14.25	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 0.0167% Middle Eastern · 1/5,998 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00106% 17/1,609,382 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,998
Admixed American	0.00833%	12,000
East Asian	0.00223%	44,882
South Asian	0.0011%	91,084
European (non-Finnish)	0.000763%	131,104

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.Ala166Thr
Coding: c.496G>A
MANE Select: NM_001972
dbSNP: rs201788817
Type: single nucleotide variant
Location: chr19:855693 (GRCh38)
Gene constraint: LOEUF 1.245 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.42 · 38 PDB
Residue 166: a disulfide bond; the peptidase s1 domain; a UniProt-annotated variant site (in scn1; the patient also carries mutation lys-116 in g6pc3)

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.Ala166= Conflicting classifications of pathogenicity ★ same residue
ELANE p.Ala166Pro 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
ELANE p.Ala57Thr Pathogenic/Likely pathogenic ★★ same condition
ELANE p.Ala61Val 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-ala166thr (accessed [today's date]).

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