Is ELANE p.Arg193Trp (c.577C>T) pathogenic?

ELANE p.Arg193Trp (c.577C>T) is classified Uncertain significance in ELANE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-14). AlphaMissense: ambiguous (0.3446); Very rare (popmax 0.0022%, sas); Associated with neutropenia, severe congenital, 1, autosomal dominant.

What condition is associated with ELANE p.Arg193Trp (c.577C>T)?

ELANE p.Arg193Trp (c.577C>T) is associated with neutropenia, severe congenital, 1, autosomal dominant, cyclic neutropenia (ClinVar).

How common is ELANE p.Arg193Trp (c.577C>T) in the general population?

ELANE p.Arg193Trp (c.577C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about ELANE p.Arg193Trp (c.577C>T)?

AlphaMissense predicts ambiguous (score 0.3446) — an in-silico prediction, not a clinical call.

ELANE p.Arg193Trp

Q: How is Autosomal dominant severe congenital neutropenia inherited?

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

c.577C>T · rs201723157 · VCV1304980

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3446 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

neutropenia, severe congenital, 1, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.3446	ambiguous
REVEL	0.5	indeterminate
SaProt	LLR -11.26	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.8	GERP 2.1, phastCons 0.84
Regional constraint	o/e 1.04	unconstrained · MANE · 3,171 bp · p 0.52 · regional, not allelic
Overall
CADD	25.0	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 0.0022% South Asian · 2/91,028 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000373% 6/1,608,624 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,514
Admixed American	0.00167%	59,998
European (non-Finnish)	0.000254%	393,318

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.Arg193Trp
Coding: c.577C>T
MANE Select: NM_001972
dbSNP: rs201723157
Type: single nucleotide variant
Location: chr19:855774 (GRCh38)
Gene constraint: LOEUF 1.245 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.42 · 38 PDB
Residue 193: a disulfide bond; a β-strand; the peptidase s1 domain; a UniProt-annotated variant site (in scn1 and ch)

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.Arg193Gln 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
ELANE p.Ala57Thr Pathogenic/Likely pathogenic ★★ same condition
ELANE p.Ala61Val Pathogenic/Likely pathogenic ★★ same condition
ELANE p.Arg103Pro 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-arg193trp (accessed [today's date]).

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