Is EDEM3 p.Asp554Val (c.1661A>T) pathogenic?

EDEM3 p.Asp554Val (c.1661A>T) is classified Uncertain significance in EDEM3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-01). AlphaMissense: likely pathogenic (0.738); Ultra-rare (popmax 0.0246%, eas); Associated with congenital disorder of glycosylation, type 2v.

What condition is associated with EDEM3 p.Asp554Val (c.1661A>T)?

EDEM3 p.Asp554Val (c.1661A>T) is associated with congenital disorder of glycosylation, type 2v (ClinVar).

How common is EDEM3 p.Asp554Val (c.1661A>T) in the general population?

EDEM3 p.Asp554Val (c.1661A>T) is ultra-rare (popmax 0.0246%, eas) (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.Asp554Val (c.1661A>T)?

AlphaMissense predicts likely pathogenic (score 0.738) — an in-silico prediction, not a clinical call.

EDEM3 p.Asp554Val

c.1661A>T · VCV3382958

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.738 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0246%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

congenital disorder of glycosylation, type 2v

Computational evidence

Protein change
AlphaMissense	0.738	likely pathogenic
REVEL	0.573	indeterminate
SaProt	LLR -6.74	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.76 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 2,044 bp · p 0.22 · regional, not allelic
Overall
CADD	25.9	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 0.0246% East Asian · 11/44,798 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.000682% 11/1,612,792 alleles · ultra-rare exomes 8/1,460,552 · genomes 3/152,240 · joint denominator

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.Asp554Val
Coding: c.1661A>T
MANE Select: NM_025191
Type: single nucleotide variant
Location: chr1:184711753 (GRCh38)
Gene constraint: LOEUF 0.671 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.50
Residue 554: 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.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 p.Pro746Ser Benign ★ ⚠ 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-asp554val (accessed [today's date]).

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