Is EDEM3 p.Thr222= (c.666A>G) pathogenic?

EDEM3 p.Thr222= (c.666A>G) is classified Likely benign in EDEM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-01). Rare (popmax 0.442%, afr).

How common is EDEM3 p.Thr222= (c.666A>G) in the general population?

EDEM3 p.Thr222= (c.666A>G) is rare (popmax 0.442%, afr) (gnomAD).

EDEM3 p.Thr222=

c.666A>G · rs111881385 · VCV2639634

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.442%, afr)

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
Constraint at this position
Conservation	phyloP -4	GERP -5.7
Overall
CADD	6.182	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.442% African / African-American · 332/75,048 alleles

Filtering AF 0.403% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.388%

Overall 0.0237% 383/1,613,914 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.442%	226
Middle Eastern	0.0495%	2,020
Admixed American	0.045%	2,223
Remaining individualsnot grpmax-eligible	0.0256%	3,906
South Asian	0.0022%	45,541
European (non-Finnish)	0.000254%	393,286

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.Thr222=
Coding: c.666A>G
MANE Select: NM_025191
dbSNP: rs111881385
Type: single nucleotide variant
Location: chr1:184726336 (GRCh38)
Gene constraint: LOEUF 0.671 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.50

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

Similar variants

EDEM3 p.Arg579Lys Uncertain significance ★★ ⚠ same type
EDEM3 p.Asn691Ser Uncertain significance ★★ ⚠ same type
EDEM3 p.Asp554Val Uncertain significance ★★ ⚠ same type
EDEM3 p.His454Gln Uncertain significance ★★ ⚠ same type
EDEM3 p.Pro574Ser Uncertain significance ★★ ⚠ same type
EDEM3 c.346-1G>A Pathogenic ★ same type
EDEM3 p.Arg265Ter Likely pathogenic ★ same type
EDEM3 p.Arg648Ter 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/edem3-p-thr222 (accessed [today's date]).

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