Is ELN p.Ala469Thr (c.1405G>A) pathogenic?

ELN p.Ala469Thr (c.1405G>A) is classified Uncertain significance in ELN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-07-07). AlphaMissense: ambiguous (0.4242); Ultra-rare (popmax 0.0242%, sas); Associated with supravalvular aortic stenosis.

What condition is associated with ELN p.Ala469Thr (c.1405G>A)?

ELN p.Ala469Thr (c.1405G>A) is associated with supravalvular aortic stenosis (ClinVar).

How common is ELN p.Ala469Thr (c.1405G>A) in the general population?

ELN p.Ala469Thr (c.1405G>A) is ultra-rare (popmax 0.0242%, sas) (gnomAD).

What do computational predictors say about ELN p.Ala469Thr (c.1405G>A)?

AlphaMissense predicts ambiguous (score 0.4242) — an in-silico prediction, not a clinical call.

ELN p.Ala469Thr

c.1405G>A · rs782700997 · VCV1982977

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4242 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0242%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

supravalvular aortic stenosis

Computational evidence

Protein change
AlphaMissense	0.4242	ambiguous
REVEL	0.167	moderately benign-leaning
SaProt	LLR -12.12	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP 5.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 41 kb · p 0.005 · regional, not allelic
Overall
CADD	24.0	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 A498T vs ClinVar A469T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0242% South Asian · 22/91,030 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.00552% 89/1,613,228 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0242%	4,138
Remaining individualsnot grpmax-eligible	0.0112%	8,915
Admixed American	0.00834%	11,996
East Asian	0.00668%	14,963
European (non-Finnish)	0.00441%	22,691

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.Ala469Thr
Coding: c.1405G>A
MANE Select: NM_000501
dbSNP: rs782700997
Type: single nucleotide variant
Location: chr7:74057687 (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.Ala469Ser Uncertain significance ★ ⚠ same residue
ELN p.Ala469Val Uncertain significance ★ ⚠ same residue
ELN p.Ala469= Likely benign ★ same residue
ELN p.Ala469_Gln470insAlaLysAlaAla 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

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-ala469thr (accessed [today's date]).

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