Is ELN p.Val285Met (c.853G>A) pathogenic?

ELN p.Val285Met (c.853G>A) is classified Conflicting classifications of pathogenicity in ELN (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-02-01). AlphaMissense: likely benign (0.2977); Ultra-rare (popmax 0.0691%, eas); Associated with cutis laxa, autosomal dominant 1.

What condition is associated with ELN p.Val285Met (c.853G>A)?

ELN p.Val285Met (c.853G>A) is associated with cutis laxa, autosomal dominant 1, supravalvular aortic stenosis (ClinVar).

How common is ELN p.Val285Met (c.853G>A) in the general population?

ELN p.Val285Met (c.853G>A) is ultra-rare (popmax 0.0691%, eas) (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.Val285Met (c.853G>A)?

AlphaMissense predicts likely benign (score 0.2977) — an in-silico prediction, not a clinical call.

ELN p.Val285Met

c.853G>A · rs199709542 · VCV912215

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2977 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0691%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cutis laxa, autosomal dominant 1

Computational evidence

Protein change
AlphaMissense	0.2977	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -12.84	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 5.1, phastCons 0.98
Regional constraint	o/e 0.91	unconstrained · MANE · 41 kb · p 0.005 · regional, not allelic
Overall
CADD	19.19	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0691% East Asian · 31/44,880 alleles

Filtering AF 0.05% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0435%

Overall 0.00384% 62/1,614,204 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0691%	1,448
Remaining individualsnot grpmax-eligible	0.0128%	7,813
African / African-American	0.004%	25,015
South Asian	0.0022%	45,542
Admixed American	0.00167%	60,034
European (non-Finnish)	0.00144%	69,414

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.Val285Met
Coding: c.853G>A
MANE Select: NM_000501
dbSNP: rs199709542
Type: single nucleotide variant
Location: chr7:74051803 (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.Val285Leu 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
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-val285met (accessed [today's date]).

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