Is ELN p.Lys724Ile (c.2171A>T) pathogenic?

ELN p.Lys724Ile (c.2171A>T) is classified Uncertain significance in ELN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-01). AlphaMissense: likely pathogenic (0.7619); Very rare (popmax 0.000169%, nfe); Associated with supravalvular aortic stenosis.

What condition is associated with ELN p.Lys724Ile (c.2171A>T)?

ELN p.Lys724Ile (c.2171A>T) is associated with supravalvular aortic stenosis (ClinVar).

How common is ELN p.Lys724Ile (c.2171A>T) in the general population?

ELN p.Lys724Ile (c.2171A>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ELN p.Lys724Ile (c.2171A>T)?

AlphaMissense predicts likely pathogenic (score 0.7619) — an in-silico prediction, not a clinical call.

ELN p.Lys724Ile

c.2171A>T · rs971612292 · VCV2413019

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7619 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

supravalvular aortic stenosis

Computational evidence

Protein change
AlphaMissense	0.7619	likely pathogenic
REVEL	0.193	benign-leaning
SaProt	LLR -10.68	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 11	GERP 6.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 41 kb · p 0.005 · regional, not allelic
Overall
CADD	24.6	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 K786I vs ClinVar K724I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,978 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,830 alleles · very rare

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.Lys724Ile
Coding: c.2171A>T
MANE Select: NM_000501
dbSNP: rs971612292
Type: single nucleotide variant
Location: chr7:74068696 (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 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-lys724ile (accessed [today's date]).

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