Is EDC4 p.Glu552Lys (c.1654G>A) pathogenic?

EDC4 p.Glu552Lys (c.1654G>A) is classified Uncertain significance in EDC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-22). AlphaMissense: likely benign (0.1687); Very rare (popmax 0.00668%, eas).

How common is EDC4 p.Glu552Lys (c.1654G>A) in the general population?

EDC4 p.Glu552Lys (c.1654G>A) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about EDC4 p.Glu552Lys (c.1654G>A)?

AlphaMissense predicts likely benign (score 0.1687) — an in-silico prediction, not a clinical call.

EDC4 p.Glu552Lys

c.1654G>A · rs374190646 · VCV2487260

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1687 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1687	likely benign
REVEL	0.161	moderately benign-leaning
SaProt	LLR -7.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,809 bp · p 0.01 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% East Asian · 3/44,900 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.0018% 29/1,613,970 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,967
European (non-Finnish)	0.0022%	45,385

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: EDC4
Protein: p.Glu552Lys
Coding: c.1654G>A
MANE Select: NM_014329
dbSNP: rs374190646
Type: single nucleotide variant
Location: chr16:67879607 (GRCh38)
Gene constraint: LOEUF 0.494 · pLI 0.59 (gnomAD)
Structure: AlphaFold pLDDT 63.18
Residue 552: the 'disordered' region

Full EDC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EDC4 p.Gly309= Benign ★★ same type
EDC4 p.Ala1030Val Uncertain significance ★ ⚠ same type
EDC4 p.Ala1036Thr Uncertain significance ★ ⚠ same type
EDC4 p.Ala1076Thr Uncertain significance ★ ⚠ same type
EDC4 p.Ala1117Asp Uncertain significance ★ ⚠ same type
EDC4 p.Ala1284Val Uncertain significance ★ ⚠ same type
EDC4 p.Ala26Gly Uncertain significance ★ ⚠ same type
EDC4 p.Ala315Val 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/edc4-p-glu552lys (accessed [today's date]).

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