Is EDC3 p.Leu463= (c.1389G>A) pathogenic?

EDC3 p.Leu463= (c.1389G>A) is classified Likely benign in EDC3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-11-12). Ultra-rare (popmax 0.045%, amr); Associated with EDC3-related disorder.

What condition is associated with EDC3 p.Leu463= (c.1389G>A)?

EDC3 p.Leu463= (c.1389G>A) is associated with EDC3-related disorder (ClinVar).

How common is EDC3 p.Leu463= (c.1389G>A) in the general population?

EDC3 p.Leu463= (c.1389G>A) is ultra-rare (popmax 0.045%, amr) (gnomAD).

EDC3 p.Leu463=

c.1389G>A · rs764673612 · VCV3045617

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.045%, amr)

Conditions

EDC3-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.20	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 0.3	GERP -3.8, phastCons 0.6
Overall
CADD	6.067	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.045% Admixed American · 27/60,008 alleles

Filtering AF 0.0317% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0273%

Overall 0.00316% 51/1,614,124 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.045%	2,223
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)	0.00186%	53,639

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: EDC3
Protein: p.Leu463=
Coding: c.1389G>A
MANE Select: NM_025083
dbSNP: rs764673612
Type: single nucleotide variant
Location: chr15:74632750 (GRCh38)
Gene constraint: LOEUF 0.656 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 77.04 · 6 PDB
Residue 463: the yjef n-terminal domain; a β-strand

Full EDC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

EDC3-related disorder

Similar variants

EDC3 p.Ser166= Likely benign same condition
EDC3 p.Thr60= Likely benign same condition
EDC3 p.Arg260Trp Uncertain significance ★★ ⚠ same type
EDC3 p.Thr273= Benign ★★ same type
EDC3 c.821-2A>C Uncertain significance ★ same type
EDC3 p.Ala129Thr Uncertain significance ★ ⚠ same type
EDC3 p.Ala172Pro Uncertain significance ★ ⚠ same type
EDC3 p.Ala312Thr Uncertain significance ★ ⚠ 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/edc3-p-leu463 (accessed [today's date]).

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