Is ELN p.Pro693Leu (c.2078C>T) pathogenic?

ELN p.Pro693Leu (c.2078C>T) is classified Uncertain significance in ELN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-30). AlphaMissense: ambiguous (0.3672); Absent from gnomAD v4.1; Associated with supravalvular aortic stenosis.

What condition is associated with ELN p.Pro693Leu (c.2078C>T)?

ELN p.Pro693Leu (c.2078C>T) is associated with supravalvular aortic stenosis (ClinVar).

How common is ELN p.Pro693Leu (c.2078C>T) in the general population?

ELN p.Pro693Leu (c.2078C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ELN p.Pro693Leu (c.2078C>T)?

AlphaMissense predicts ambiguous (score 0.3672) — an in-silico prediction, not a clinical call.

ELN p.Pro693Leu

c.2078C>T · VCV4752894

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3672 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

supravalvular aortic stenosis

Computational evidence

Protein change
AlphaMissense	0.3672	ambiguous
REVEL	0.19	benign-leaning
SaProt	LLR -8.40	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.3	GERP 4.3, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 41 kb · p 0.005 · regional, not allelic
Overall
CADD	23.5	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 P755L vs ClinVar P693L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ELN
Protein: p.Pro693Leu
Coding: c.2078C>T
MANE Select: NM_000501
Type: single nucleotide variant
Location: chr7:74065989 (GRCh38)
Gene constraint: LOEUF 0.696 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 36.20
Residue 693: a modified residue (allysine)

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

Similar variants

ELN p.Pro693Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
ELN p.Pro693fs Likely pathogenic ★ 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-pro693leu (accessed [today's date]).

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