Is ELANE p.Asp243Tyr (c.727G>T) pathogenic?

ELANE p.Asp243Tyr (c.727G>T) is classified Uncertain significance in ELANE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-23). AlphaMissense: likely benign (0.2504); Very rare (popmax 0.005%, amr); Associated with neutropenia, severe congenital, 1, autosomal dominant.

What condition is associated with ELANE p.Asp243Tyr (c.727G>T)?

ELANE p.Asp243Tyr (c.727G>T) is associated with neutropenia, severe congenital, 1, autosomal dominant, cyclic neutropenia (ClinVar).

How common is ELANE p.Asp243Tyr (c.727G>T) in the general population?

ELANE p.Asp243Tyr (c.727G>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about ELANE p.Asp243Tyr (c.727G>T)?

AlphaMissense predicts likely benign (score 0.2504) — an in-silico prediction, not a clinical call.

ELANE p.Asp243Tyr

Q: How is Autosomal dominant severe congenital neutropenia inherited?

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

c.727G>T · rs752022665 · VCV647853

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2504 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neutropenia, severe congenital, 1, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.2504	likely benign
REVEL	0.313	indeterminate
SaProt	LLR -7.00	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 0.24	GERP -4.1, phastCons 0.017
Regional constraint	o/e 1.04	unconstrained · MANE · 3,171 bp · p 0.52 · regional, not allelic
Overall
CADD	10.48	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.005% Admixed American · 3/60,016 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000479% 7/1,461,074 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,005
Remaining individualsnot grpmax-eligible	0.0032%	31,250
European (non-Finnish)	0.000169%	590,005

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.Asp243Tyr
Coding: c.727G>T
MANE Select: NM_001972
dbSNP: rs752022665
Type: single nucleotide variant
Location: chr19:856087 (GRCh38)
Gene constraint: LOEUF 1.245 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.42 · 38 PDB
Residue 243: an α-helix; 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.Asp243Gly Uncertain significance ★ ⚠ same residue
ELANE p.Asp243Asn 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-asp243tyr (accessed [today's date]).

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