Is EDEM2 p.Arg224Cys (c.670C>T) pathogenic?

EDEM2 p.Arg224Cys (c.670C>T) is classified Uncertain significance in EDEM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-28). AlphaMissense: likely benign (0.1824); Very rare (popmax 0.00668%, eas).

How common is EDEM2 p.Arg224Cys (c.670C>T) in the general population?

EDEM2 p.Arg224Cys (c.670C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about EDEM2 p.Arg224Cys (c.670C>T)?

AlphaMissense predicts likely benign (score 0.1824) — an in-silico prediction, not a clinical call.

EDEM2 p.Arg224Cys

c.670C>T · rs368321216 · VCV2457254

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1824 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1824	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -11.20	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP 2.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 32 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	29.6	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 0.00668% East Asian · 3/44,880 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00105% 17/1,613,702 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,960
African / African-American	0.004%	25,006
Admixed American	0.00333%	30,007
Remaining individualsnot grpmax-eligible	0.0016%	62,462
European (non-Finnish)	0.000678%	147,503

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: EDEM2
Protein: p.Arg224Cys
Coding: c.670C>T
MANE Select: NM_018217
dbSNP: rs368321216
Type: single nucleotide variant
Location: chr20:35134770 (GRCh38)
Gene constraint: LOEUF 0.749 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.61

Full EDEM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EDEM2 p.Arg224His Uncertain significance ★ ⚠ same residue
EDEM2 p.Ala251Thr Uncertain significance ★ ⚠ same type
EDEM2 p.Ala484Thr Uncertain significance ★ ⚠ same type
EDEM2 p.Ala529Glu Uncertain significance ★ ⚠ same type
EDEM2 p.Ala81Thr Uncertain significance ★ ⚠ same type
EDEM2 p.Arg219Thr Uncertain significance ★ ⚠ same type
EDEM2 p.Arg229Gln Uncertain significance ★ ⚠ same type
EDEM2 p.Arg292Cys 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/edem2-p-arg224cys (accessed [today's date]).

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