Is ELANE p.Thr58Ile (c.173C>T) pathogenic?

ELANE p.Thr58Ile (c.173C>T) is classified Uncertain significance in ELANE (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-21). AlphaMissense: likely pathogenic (0.6481); Ultra-rare (popmax 0.0168%, mid); Associated with neutropenia, severe congenital, 1, autosomal dominant.

What condition is associated with ELANE p.Thr58Ile (c.173C>T)?

ELANE p.Thr58Ile (c.173C>T) is associated with neutropenia, severe congenital, 1, autosomal dominant, cyclic neutropenia (ClinVar).

How common is ELANE p.Thr58Ile (c.173C>T) in the general population?

ELANE p.Thr58Ile (c.173C>T) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

What do computational predictors say about ELANE p.Thr58Ile (c.173C>T)?

AlphaMissense predicts likely pathogenic (score 0.6481) — an in-silico prediction, not a clinical call.

ELANE p.Thr58Ile

Q: How is Autosomal dominant severe congenital neutropenia inherited?

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

c.173C>T · rs764500411 · VCV2151751

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6481 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neutropenia, severe congenital, 1, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.6481	likely pathogenic
REVEL	0.642	indeterminate
SaProt	LLR -10.02	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP -1.1, phastCons 0.95
Regional constraint	o/e 0.31	constrained · MANE · 62 bp · p 0.00023 · regional, not allelic
Overall
CADD	21.6	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

Grpmax group 0.0168% Middle Eastern · 1/5,960 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00028% 4/1,430,850 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,960
European (non-Finnish)	0.000256%	390,472

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.Thr58Ile
Coding: c.173C>T
MANE Select: NM_001972
dbSNP: rs764500411
Type: single nucleotide variant
Location: chr19:852981 (GRCh38)
Gene constraint: LOEUF 1.245 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.42 · 38 PDB
Residue 58: a disulfide bond; a β-strand; 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.Thr58= Benign/Likely benign ★★ same residue
ELANE p.Thr58Pro Uncertain significance ★ ⚠ same residue
ELANE p.Thr58Ser 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-thr58ile (accessed [today's date]).

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