Is ELN p.Ala458Glu (c.1373C>A) pathogenic?

ELN p.Ala458Glu (c.1373C>A) is classified Uncertain significance in ELN (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-17). AlphaMissense: ambiguous (0.4776); Ultra-rare (popmax 0.0641%, afr); Associated with cutis laxa, autosomal dominant 1.

What condition is associated with ELN p.Ala458Glu (c.1373C>A)?

ELN p.Ala458Glu (c.1373C>A) is associated with cutis laxa, autosomal dominant 1, supravalvular aortic stenosis, Williams syndrome (ClinVar).

How common is ELN p.Ala458Glu (c.1373C>A) in the general population?

ELN p.Ala458Glu (c.1373C>A) is ultra-rare (popmax 0.0641%, afr) (gnomAD).

How is Autosomal dominant cutis laxa inherited?

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

What do computational predictors say about ELN p.Ala458Glu (c.1373C>A)?

AlphaMissense predicts ambiguous (score 0.4776) — an in-silico prediction, not a clinical call.

ELN p.Ala458Glu

c.1373C>A · rs149117932 · VCV1416484

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4776 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0641%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

cutis laxa, autosomal dominant 1

Computational evidence

Protein change
AlphaMissense	0.4776	ambiguous
REVEL	0.208	benign-leaning
SaProt	LLR -7.54	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 5.9, phastCons 0.98
Regional constraint	o/e 0.91	unconstrained · MANE · 41 kb · p 0.005 · regional, not allelic
Overall
CADD	19.77	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A487E vs ClinVar A458E) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0641% African / African-American · 48/74,924 alleles

Filtering AF 0.0496% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0444%

Overall 0.00322% 52/1,613,808 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0641%	1,561
Admixed American	0.00333%	30,000
European (non-Finnish)	0.000169%	590,012

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: ELN
Protein: p.Ala458Glu
Coding: c.1373C>A
MANE Select: NM_000501
dbSNP: rs149117932
Type: single nucleotide variant
Location: chr7:74057655 (GRCh38)
Gene constraint: LOEUF 0.696 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 36.20

Full ELN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cutis laxa, autosomal dominant 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: supravalvular aortic stenosis Williams syndrome

For Autosomal dominant cutis laxa (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

ELN p.Ala458Gly Uncertain significance ★ ⚠ same residue
ELN p.Ala458Thr Uncertain significance ★ ⚠ same residue
ELN p.Ala458Val Uncertain significance ★ ⚠ same residue
ELN c.377-2A>G Pathogenic/Likely pathogenic ★★ same condition
ELN c.643+1G>C Likely pathogenic ★★ same condition
ELN c.686-2A>G Likely pathogenic ★★ same condition
ELN c.800-1G>A Pathogenic/Likely pathogenic ★★ same condition
ELN c.800-2A>G 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/eln-p-ala458glu (accessed [today's date]).

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