Is ELN p.Pro433Leu (c.1298C>T) pathogenic?

ELN p.Pro433Leu (c.1298C>T) is classified Uncertain significance in ELN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-18). AlphaMissense: likely pathogenic (0.5907); Ultra-rare (popmax 0.0165%, mid); Associated with supravalvular aortic stenosis.

What condition is associated with ELN p.Pro433Leu (c.1298C>T)?

ELN p.Pro433Leu (c.1298C>T) is associated with supravalvular aortic stenosis (ClinVar).

How common is ELN p.Pro433Leu (c.1298C>T) in the general population?

ELN p.Pro433Leu (c.1298C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ELN p.Pro433Leu (c.1298C>T)?

AlphaMissense predicts likely pathogenic (score 0.5907) — an in-silico prediction, not a clinical call.

ELN p.Pro433Leu

c.1298C>T · rs782575011 · VCV2752619

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5907 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

supravalvular aortic stenosis

Computational evidence

Protein change
AlphaMissense	0.5907	likely pathogenic
REVEL	0.053	moderately benign-leaning
SaProt	LLR -11.24	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.97	GERP 3.5, phastCons 0.89
Regional constraint	o/e 0.91	unconstrained · MANE · 41 kb · p 0.005 · regional, not allelic
Overall
CADD	19.85	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 0.0165% Middle Eastern · 1/6,068 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00186% 30/1,613,550 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,699
Middle Easterngrpmax	0.0165%	6,068
European (non-Finnish)	0.00161%	62,095
Remaining individualsnot grpmax-eligible	0.0016%	62,448
African / African-American	0.00134%	74,838

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro433Leu
Coding: c.1298C>T
MANE Select: NM_000501
dbSNP: rs782575011
Type: single nucleotide variant
Location: chr7:74056418 (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

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

Similar variants

ELN p.Pro433= 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-pro433leu (accessed [today's date]).

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