Is ELN p.Lys463Arg (c.1388A>G) pathogenic?

ELN p.Lys463Arg (c.1388A>G) is classified Benign/Likely benign in ELN (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.1723); Low-frequency (popmax 1.73%, afr); Associated with cutis laxa, autosomal dominant 1.

What condition is associated with ELN p.Lys463Arg (c.1388A>G)?

ELN p.Lys463Arg (c.1388A>G) is associated with cutis laxa, autosomal dominant 1, supravalvular aortic stenosis (ClinVar).

How common is ELN p.Lys463Arg (c.1388A>G) in the general population?

ELN p.Lys463Arg (c.1388A>G) is low-frequency (popmax 1.73%, 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.Lys463Arg (c.1388A>G)?

AlphaMissense predicts likely benign (score 0.1723) — an in-silico prediction, not a clinical call.

ELN p.Lys463Arg

c.1388A>G · rs34945509 · VCV416912

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1723 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.73%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cutis laxa, autosomal dominant 1

Computational evidence

Protein change
AlphaMissense	0.1723	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -9.71	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 5.4	GERP 4.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 41 kb · p 0.005 · regional, not allelic
Overall
CADD	16.32	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 K492R vs ClinVar K463R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.73% African / African-American · 1,294/74,974 alleles

Filtering AF 1.65% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.62%

Overall 0.0955% 1,541/1,613,616 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.73%	58
Remaining individualsnot grpmax-eligible	0.133%	752
Admixed American	0.123%	811
Middle Eastern	0.122%	821
South Asian	0.00769%	13,006
European (non-Finnish)	0.00644%	15,526

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.Lys463Arg
Coding: c.1388A>G
MANE Select: NM_000501
dbSNP: rs34945509
Type: single nucleotide variant
Location: chr7:74057670 (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

For Autosomal dominant cutis laxa (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

ELN p.Lys463= Likely benign 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
ELN c.800-3C>G Pathogenic ★★ same condition
ELN c.82+1G>A 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/eln-p-lys463arg (accessed [today's date]).

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