Is EDEM3 p.Pro746Ser (c.2236C>T) pathogenic?

EDEM3 p.Pro746Ser (c.2236C>T) is classified Benign in EDEM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-04). AlphaMissense: likely pathogenic (0.8534); Low-frequency (popmax 1.88%, nfe); Associated with congenital disorder of glycosylation, type 2v.

What condition is associated with EDEM3 p.Pro746Ser (c.2236C>T)?

EDEM3 p.Pro746Ser (c.2236C>T) is associated with congenital disorder of glycosylation, type 2v (ClinVar).

How common is EDEM3 p.Pro746Ser (c.2236C>T) in the general population?

EDEM3 p.Pro746Ser (c.2236C>T) is low-frequency (popmax 1.88%, nfe) (gnomAD).

How is EDEM3-CDG inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about EDEM3 p.Pro746Ser (c.2236C>T)?

AlphaMissense predicts likely pathogenic (score 0.8534) — an in-silico prediction, not a clinical call.

EDEM3 p.Pro746Ser

c.2236C>T · rs78444298 · VCV3068615

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8534 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.88%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital disorder of glycosylation, type 2v

Computational evidence

Protein change
AlphaMissense	0.8534	likely pathogenic
REVEL	0.245	benign-leaning
SaProt	LLR -6.90	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.26	acceptor loss · deltas
Pangolin	Δ0.27	loss · gain 0.21 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 16 kb · p 0.0044 · regional, not allelic
Overall
CADD	25.0	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 1.88% European (non-Finnish) · 22,195/1,178,916 alleles

Filtering AF 1.86% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.85%

Overall 1.6% 25,833/1,611,476 alleles · low-frequency

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	2.09%	48
European (non-Finnish)grpmax	1.88%	53
Finnishnot grpmax-eligible	1.65%	61
Remaining individualsnot grpmax-eligible	1.34%	75
South Asian	0.661%	151
Admixed American	0.541%	185
Amishnot grpmax-eligible	0.329%	304
African / African-American	0.257%	389
Middle Eastern	0.215%	466
East Asian	0.00448%	22,329

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro746Ser
Coding: c.2236C>T
MANE Select: NM_025191
dbSNP: rs78444298
Type: single nucleotide variant
Location: chr1:184702964 (GRCh38)
Gene constraint: LOEUF 0.671 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.50
Residue 746: the pa domain; 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

congenital disorder of glycosylation, type 2v — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For EDEM3-CDG (Orphanet):

Inheritance: Autosomal recessive

Similar variants

EDEM3 p.Asp554Val Uncertain significance ★★ ⚠ same condition
EDEM3 p.Arg265Ter Likely pathogenic ★ same condition
EDEM3 c.1692-28A>T Uncertain significance ★ same condition
EDEM3 c.306-3T>A Uncertain significance ★ same condition
EDEM3 p.Ala99Thr Uncertain significance ★ ⚠ same condition
EDEM3 p.Val96Ile Uncertain significance ★ ⚠ same condition
EDEM3 c.853+1G>T Pathogenic same condition
EDEM3 p.Arg314Ter Pathogenic 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-pro746ser (accessed [today's date]).

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