Is ELN p.Val503Met (c.1507G>A) pathogenic?

ELN p.Val503Met (c.1507G>A) is classified Benign/Likely benign in ELN (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-27). AlphaMissense: ambiguous (0.4772); Ultra-rare (popmax 0.0875%, nfe); Associated with cutis laxa, autosomal dominant 1.

What condition is associated with ELN p.Val503Met (c.1507G>A)?

ELN p.Val503Met (c.1507G>A) is associated with cutis laxa, autosomal dominant 1, supravalvular aortic stenosis (ClinVar).

How common is ELN p.Val503Met (c.1507G>A) in the general population?

ELN p.Val503Met (c.1507G>A) is ultra-rare (popmax 0.0875%, nfe) (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.Val503Met (c.1507G>A)?

AlphaMissense predicts ambiguous (score 0.4772) — an in-silico prediction, not a clinical call.

ELN p.Val503Met

c.1507G>A · rs41523046 · VCV360656

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

ambiguous

0.4772 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0875%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

cutis laxa, autosomal dominant 1

Computational evidence

Protein change
AlphaMissense	0.4772	ambiguous
REVEL	0.063	moderately benign-leaning
SaProt	LLR -14.44	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.14	GERP 3.9
Regional constraint	o/e 0.91	unconstrained · MANE · 41 kb · p 0.005 · regional, not allelic
Overall
CADD	17.27	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 V532M vs ClinVar V503M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0875% European (non-Finnish) · 1,032/1,179,692 alleles

Filtering AF 0.083% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0813%

Overall 0.069% 1,113/1,613,372 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0875%	1,143
Remaining individualsnot grpmax-eligible	0.0672%	1,488
Finnishnot grpmax-eligible	0.0219%	4,570
Middle Eastern	0.0165%	6,060
South Asian	0.011%	9,103
African / African-American	0.0107%	9,357
Admixed American	0.00834%	11,993
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,508

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.Val503Met
Coding: c.1507G>A
MANE Select: NM_000501
dbSNP: rs41523046
Type: single nucleotide variant
Location: chr7:74059978 (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.Val503Leu Uncertain significance ★ ⚠ same residue
ELN p.Val503= 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

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-val503met (accessed [today's date]).

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