Is EDEM3 p.Ile620Val (c.1858A>G) pathogenic?

EDEM3 p.Ile620Val (c.1858A>G) is classified Uncertain significance in EDEM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely benign (0.0519); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with EDEM3 p.Ile620Val (c.1858A>G)?

EDEM3 p.Ile620Val (c.1858A>G) is associated with Inborn genetic diseases (ClinVar).

How common is EDEM3 p.Ile620Val (c.1858A>G) in the general population?

EDEM3 p.Ile620Val (c.1858A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about EDEM3 p.Ile620Val (c.1858A>G)?

AlphaMissense predicts likely benign (score 0.0519) — an in-silico prediction, not a clinical call.

EDEM3 p.Ile620Val

c.1858A>G · rs368655971 · VCV2365226

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0519 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0519	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -5.10	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 -0.16	GERP -1.7, phastCons 0.077
Regional constraint	o/e 0.86	unconstrained · MANE · 16 kb · p 0.0044 · regional, not allelic
Overall
CADD	10.41	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 0.0165% Middle Eastern · 1/6,068 alleles

Filtering AF 0.0109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.01% 161/1,609,868 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,068
European (non-Finnish)	0.0126%	7,967
African / African-American	0.00537%	18,626
Admixed American	0.0034%	29,377
Remaining individualsnot grpmax-eligible	0.00321%	31,179
East Asian	0.00223%	44,838
South Asian	0.00223%	44,930
Finnishnot grpmax-eligible	0.00156%	64,018

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: EDEM3
Protein: p.Ile620Val
Coding: c.1858A>G
MANE Select: NM_025191
dbSNP: rs368655971
Type: single nucleotide variant
Location: chr1:184708332 (GRCh38)
Gene constraint: LOEUF 0.671 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.50
Residue 620: a UniProt-annotated variant site (in cdg2v; uncertain significance)

Full EDEM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EDEM3 p.Ile620Thr Uncertain significance ★ ⚠ same residue
EDEM3 p.Arg579Lys Uncertain significance ★★ ⚠ same condition
EDEM3 p.Asn691Ser Uncertain significance ★★ ⚠ same condition
EDEM3 p.His454Gln Uncertain significance ★★ ⚠ same condition
EDEM3 p.Pro574Ser Uncertain significance ★★ ⚠ same condition
EDEM3 p.Ala17Gly Conflicting classifications of pathogenicity ★ ⚠ same condition
EDEM3 p.Ala245Thr Uncertain significance ★ ⚠ same condition
EDEM3 p.Ala41Val Uncertain significance ★ ⚠ 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/edem3-p-ile620val (accessed [today's date]).

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