Is CDON p.Cys333= (c.999C>T) pathogenic?

CDON p.Cys333= (c.999C>T) is classified Likely benign in CDON (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-15). Ultra-rare (popmax 0.0357%, eas); Associated with holoprosencephaly 11.

What condition is associated with CDON p.Cys333= (c.999C>T)?

CDON p.Cys333= (c.999C>T) is associated with holoprosencephaly 11 (ClinVar).

How common is CDON p.Cys333= (c.999C>T) in the general population?

CDON p.Cys333= (c.999C>T) is ultra-rare (popmax 0.0357%, eas) (gnomAD).

CDON p.Cys333=

c.999C>T · rs201493965 · VCV737109

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0357%, eas)

Conditions

holoprosencephaly 11

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -4.1, phastCons 1
Overall
CADD	8.741	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0357% East Asian · 16/44,854 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.00266% 43/1,613,984 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0357%	2,803
Remaining individualsnot grpmax-eligible	0.008%	12,501
Finnishnot grpmax-eligible	0.00312%	32,017
African / African-American	0.00267%	37,513
European (non-Finnish)	0.00153%	65,550

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.Cys333=
Coding: c.999C>T
MANE Select: NM_001378964
dbSNP: rs201493965
Type: single nucleotide variant
Location: chr11:126015440 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.62 · 3 PDB
Residue 333: a disulfide bond; the ig-like c2-type 4 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-cys333 (accessed [today's date]).

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