Is CDON p.Glu493Asp (c.1479A>C) pathogenic?

CDON p.Glu493Asp (c.1479A>C) is classified Uncertain significance in CDON (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-27). AlphaMissense: ambiguous (0.3583); Very rare (popmax 0.00333%, amr); Associated with holoprosencephaly 11.

What condition is associated with CDON p.Glu493Asp (c.1479A>C)?

CDON p.Glu493Asp (c.1479A>C) is associated with holoprosencephaly 11 (ClinVar).

How common is CDON p.Glu493Asp (c.1479A>C) in the general population?

CDON p.Glu493Asp (c.1479A>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CDON p.Glu493Asp (c.1479A>C)?

AlphaMissense predicts ambiguous (score 0.3583) — an in-silico prediction, not a clinical call.

CDON p.Glu493Asp

c.1479A>C · VCV4737104

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3583 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

holoprosencephaly 11

Computational evidence

Protein change
AlphaMissense	0.3583	ambiguous
REVEL	0.219	benign-leaning
SaProt	LLR -7.33	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -3.1
Regional constraint	o/e 0.93	unconstrained · MANE · 63 kb · p 0.0032 · regional, not allelic
Overall
CADD	0.192	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 0.00333% Admixed American · 2/60,022 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000137% 2/1,461,820 alleles · very rare

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: CDON
Protein: p.Glu493Asp
Coding: c.1479A>C
MANE Select: NM_001378964
Type: single nucleotide variant
Location: chr11:126010414 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.62 · 3 PDB
Residue 493: a disulfide bond; the ig-like c2-type 5 domain

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

Disease context

holoprosencephaly 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDON c.3276+1G>T Uncertain significance ★★ same condition
CDON c.640+1G>A Uncertain significance ★★ same condition
CDON c.*1805A>G Uncertain significance ★★ same condition
CDON c.*1816C>T Uncertain significance ★★ same condition
CDON c.*2349A>C Uncertain significance ★★ same condition
CDON c.*2377T>C Uncertain significance ★★ same condition
CDON c.*2760A>G Uncertain significance ★★ same condition
CDON p.Ala1099Val Uncertain significance ★★ ⚠ 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/cdon-p-glu493asp (accessed [today's date]).

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