Is EDEM3 p.Arg648Ter (c.1942C>T) pathogenic?

EDEM3 p.Arg648Ter (c.1942C>T) is classified Pathogenic in EDEM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-01). Very rare (popmax 0.00223%, eas).

How common is EDEM3 p.Arg648Ter (c.1942C>T) in the general population?

EDEM3 p.Arg648Ter (c.1942C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

EDEM3 p.Arg648Ter

c.1942C>T · rs149304336 · VCV2639631

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 17 of 20
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.1, phastCons 1
Overall
CADD	41.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,852 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,461,282 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,852
European (non-Finnish)	0.000254%	393,281

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.Arg648Ter
Coding: c.1942C>T
MANE Select: NM_025191
dbSNP: rs149304336
Type: single nucleotide variant
Location: chr1:184708248 (GRCh38)
Gene constraint: LOEUF 0.671 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.50
Residue 648: a UniProt-annotated variant site (in cdg2v; uncertain significance)

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 c.1692-28A>T 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/edem3-p-arg648ter (accessed [today's date]).

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