Is ELN p.Val515Met (c.1543G>A) pathogenic?

ELN p.Val515Met (c.1543G>A) is classified Conflicting classifications of pathogenicity in ELN (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-04-01). AlphaMissense: ambiguous (0.4743); Ultra-rare (popmax 0.0103%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ELN p.Val515Met (c.1543G>A)?

ELN p.Val515Met (c.1543G>A) is associated with Inborn genetic diseases, cutis laxa, autosomal dominant 1, supravalvular aortic stenosis (ClinVar).

How common is ELN p.Val515Met (c.1543G>A) in the general population?

ELN p.Val515Met (c.1543G>A) is ultra-rare (popmax 0.0103%, nfe) (gnomAD).

What do computational predictors say about ELN p.Val515Met (c.1543G>A)?

AlphaMissense predicts ambiguous (score 0.4743) — an in-silico prediction, not a clinical call.

ELN p.Val515Met

c.1543G>A · rs376258672 · VCV1008316

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4743 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4743	ambiguous
REVEL	0.053	moderately benign-leaning
SaProt	LLR -13.63	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 -0.57	GERP 0.62
Regional constraint	o/e 0.91	unconstrained · MANE · 41 kb · p 0.005 · regional, not allelic
Overall
CADD	7.604	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 V544M vs ClinVar V515M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0103% European (non-Finnish) · 121/1,179,996 alleles

Filtering AF 0.00876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0082%

Overall 0.00818% 132/1,614,036 alleles · ultra-rare exomes 122/1,461,880 · genomes 10/152,156 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0103%	9,752
African / African-American	0.00667%	14,999
Remaining individualsnot grpmax-eligible	0.0064%	15,627
Admixed American	0.00333%	30,003

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.Val515Met
Coding: c.1543G>A
MANE Select: NM_000501
dbSNP: rs376258672
Type: single nucleotide variant
Location: chr7:74060014 (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

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

Also linked: cutis laxa, autosomal dominant 1 supravalvular aortic stenosis Williams syndrome

Similar variants

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
ELN c.889+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-val515met (accessed [today's date]).

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