Is ELN p.Ala447Thr (c.1339G>A) pathogenic?

ELN p.Ala447Thr (c.1339G>A) is classified Uncertain significance in ELN (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-08-29). AlphaMissense: ambiguous (0.5561); Ultra-rare (popmax 0.0212%, nfe); Associated with ELN-related disorder.

What condition is associated with ELN p.Ala447Thr (c.1339G>A)?

ELN p.Ala447Thr (c.1339G>A) is associated with ELN-related disorder, cutis laxa, autosomal dominant 1, supravalvular aortic stenosis (ClinVar).

How common is ELN p.Ala447Thr (c.1339G>A) in the general population?

ELN p.Ala447Thr (c.1339G>A) is ultra-rare (popmax 0.0212%, nfe) (gnomAD).

What do computational predictors say about ELN p.Ala447Thr (c.1339G>A)?

AlphaMissense predicts ambiguous (score 0.5561) — an in-silico prediction, not a clinical call.

ELN p.Ala447Thr

c.1339G>A · rs139335797 · VCV360654

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.5561 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0212%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

ELN-related disorder

Computational evidence

Protein change
AlphaMissense	0.5561	ambiguous
REVEL	0.216	benign-leaning
SaProt	LLR -11.60	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 9	GERP 6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 41 kb · p 0.005 · regional, not allelic
Overall
CADD	25.0	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 0.0212% European (non-Finnish) · 250/1,179,992 alleles

Filtering AF 0.019% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.0172% 278/1,613,644 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0212%	4,720
South Asian	0.0187%	5,358
Middle Eastern	0.0165%	6,062
African / African-American	0.00667%	14,999
Remaining individualsnot grpmax-eligible	0.0064%	15,624
East Asian	0.00223%	44,870

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.Ala447Thr
Coding: c.1339G>A
MANE Select: NM_000501
dbSNP: rs139335797
Type: single nucleotide variant
Location: chr7:74056695 (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

ELN-related disorder

Also linked: cutis laxa, autosomal dominant 1 supravalvular aortic stenosis

Similar variants

ELN p.Ala447= 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-ala447thr (accessed [today's date]).

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