Is ELN p.Pro427= (c.1281C>T) pathogenic?

ELN p.Pro427= (c.1281C>T) is classified Conflicting classifications of pathogenicity in ELN (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-01-26). Very rare (popmax 0.00501%, amr); Associated with supravalvular aortic stenosis.

What condition is associated with ELN p.Pro427= (c.1281C>T)?

ELN p.Pro427= (c.1281C>T) is associated with supravalvular aortic stenosis, cutis laxa, autosomal dominant 1 (ClinVar).

How common is ELN p.Pro427= (c.1281C>T) in the general population?

ELN p.Pro427= (c.1281C>T) is very rare (popmax 0.00501%, amr) (gnomAD).

ELN p.Pro427=

c.1281C>T · rs376496267 · VCV360651

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Conditions

supravalvular aortic stenosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -9.8
Overall
CADD	5.253	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00501% Admixed American · 3/59,938 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00149% 24/1,613,452 alleles · very rare exomes 23/1,461,452 · genomes 1/152,000 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00501%	19,979
South Asian	0.0022%	45,530
European (non-Finnish)	0.00153%	65,539
African / African-American	0.00134%	74,844

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.Pro427=
Coding: c.1281C>T
MANE Select: NM_000501
dbSNP: rs376496267
Type: single nucleotide variant
Location: chr7:74056401 (GRCh38)
Gene constraint: LOEUF 0.696 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 36.20
Residue 427: a modified residue (4-hydroxyproline; partial)

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

Disease context

supravalvular aortic stenosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cutis laxa, autosomal dominant 1

Similar variants

ELN p.Pro427Ala Benign/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-pro427 (accessed [today's date]).

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