Is ELN p.Ala445Asp (c.1334C>A) pathogenic?

ELN p.Ala445Asp (c.1334C>A) is classified Uncertain significance in ELN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-17). AlphaMissense: likely pathogenic (0.9629); Very rare (popmax 0.00133%, afr).

How common is ELN p.Ala445Asp (c.1334C>A) in the general population?

ELN p.Ala445Asp (c.1334C>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ELN p.Ala445Asp (c.1334C>A)?

AlphaMissense predicts likely pathogenic (score 0.9629) — an in-silico prediction, not a clinical call.

ELN p.Ala445Asp

c.1334C>A · VCV3899431

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9629 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9629	likely pathogenic · top 3% in ELN
REVEL	0.113	moderately benign-leaning
SaProt	LLR -15.59	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 5.1	GERP 5.5, 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 0.00133% African / African-American · 1/74,940 alleles

Overall 0.000657% 1/152,182 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.Ala445Asp
Coding: c.1334C>A
MANE Select: NM_000501
Type: single nucleotide variant
Location: chr7:74056690 (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

Similar variants

ELN c.134-1G>A Likely pathogenic ★★ same type
ELN c.377-2A>G Pathogenic/Likely pathogenic ★★ same type
ELN c.643+1G>A Pathogenic/Likely pathogenic ★★ same type
ELN c.643+1G>C Likely pathogenic ★★ same type
ELN c.686-2A>G Likely pathogenic ★★ same type
ELN c.800-1G>A Pathogenic/Likely pathogenic ★★ same type
ELN c.800-2A>G Pathogenic ★★ same type
ELN c.800-3C>G Pathogenic ★★ same type

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-ala445asp (accessed [today's date]).

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