Is ELANE p.Arg248His (c.743G>A) pathogenic?

ELANE p.Arg248His (c.743G>A) is classified Uncertain significance in ELANE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-14). AlphaMissense: likely benign (0.1047); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with ELANE p.Arg248His (c.743G>A)?

ELANE p.Arg248His (c.743G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ELANE p.Arg248His (c.743G>A) in the general population?

ELANE p.Arg248His (c.743G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ELANE p.Arg248His (c.743G>A)?

AlphaMissense predicts likely benign (score 0.1047) — an in-silico prediction, not a clinical call.

ELANE p.Arg248His

c.743G>A · VCV3778432

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1047 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1047	likely benign
REVEL	0.23	benign-leaning
SaProt	LLR -7.97	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 1.5	GERP -4.1, phastCons 0.003
Regional constraint	o/e 1.04	unconstrained · MANE · 3,171 bp · p 0.52 · regional, not allelic
Overall
CADD	17.07	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 0.00133% African / African-American · 1/75,028 alleles

Overall 0.000205% 3/1,460,922 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,028
South Asian	0.0011%	91,084
European (non-Finnish)	8.47e-05%	1,180,032

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.Arg248His
Coding: c.743G>A
MANE Select: NM_001972
Type: single nucleotide variant
Location: chr19:856103 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ELANE p.Arg248Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
ELANE p.Arg248Gly Uncertain significance ★ ⚠ same residue
ELANE p.Arg248Ser Uncertain significance ★ ⚠ same residue
ELANE p.Arg248= Likely benign ★ same residue
ELANE p.Ala40Val Uncertain significance ★★ ⚠ same condition
ELANE p.Ala68Asp Uncertain significance ★★ ⚠ same condition
ELANE p.Ala79Thr Uncertain significance ★★ ⚠ same condition
ELANE p.Arg183Cys Uncertain significance ★★ ⚠ 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-arg248his (accessed [today's date]).

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