Is ELN p.Ala306Thr (c.916G>A) pathogenic?

ELN p.Ala306Thr (c.916G>A) is classified Uncertain significance in ELN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-30). AlphaMissense: ambiguous (0.3678); Very rare (popmax 0.000678%, nfe); Associated with supravalvular aortic stenosis.

What condition is associated with ELN p.Ala306Thr (c.916G>A)?

ELN p.Ala306Thr (c.916G>A) is associated with supravalvular aortic stenosis (ClinVar).

How common is ELN p.Ala306Thr (c.916G>A) in the general population?

ELN p.Ala306Thr (c.916G>A) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about ELN p.Ala306Thr (c.916G>A)?

AlphaMissense predicts ambiguous (score 0.3678) — an in-silico prediction, not a clinical call.

ELN p.Ala306Thr

c.916G>A · VCV3620371

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3678 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

supravalvular aortic stenosis

Computational evidence

Protein change
AlphaMissense	0.3678	ambiguous
REVEL	0.204	benign-leaning
SaProt	LLR -10.93	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 5	GERP 5.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 41 kb · p 0.005 · regional, not allelic
Overall
CADD	25.1	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 0.000678% European (non-Finnish) · 8/1,179,918 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000548% 8/1,460,406 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.Ala306Thr
Coding: c.916G>A
MANE Select: NM_000501
Type: single nucleotide variant
Location: chr7:74051950 (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.Ala306Val 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
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-ala306thr (accessed [today's date]).

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