Is CDON p.Ser659= (c.1977C>T) pathogenic?

CDON p.Ser659= (c.1977C>T) is classified Benign/Likely benign in CDON (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-25). Ultra-rare (popmax 0.0802%, eas); Associated with holoprosencephaly 11.

What condition is associated with CDON p.Ser659= (c.1977C>T)?

CDON p.Ser659= (c.1977C>T) is associated with holoprosencephaly 11 (ClinVar).

How common is CDON p.Ser659= (c.1977C>T) in the general population?

CDON p.Ser659= (c.1977C>T) is ultra-rare (popmax 0.0802%, eas) (gnomAD).

CDON p.Ser659=

c.1977C>T · rs563267429 · VCV303506

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0802%, eas)

Conditions

holoprosencephaly 11

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.083	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -4.1
Overall
CADD	5.531	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0802% East Asian · 36/44,876 alleles

Filtering AF 0.0595% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0524%

Overall 0.00465% 75/1,614,030 alleles · ultra-rare exomes 69/1,461,822 · genomes 6/152,208 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0802%	1,247
South Asian	0.0329%	3,036
Remaining individualsnot grpmax-eligible	0.0048%	20,836
Admixed American	0.00167%	60,004
European (non-Finnish)	0.000424%	235,998

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.Ser659=
Coding: c.1977C>T
MANE Select: NM_001378964
dbSNP: rs563267429
Type: single nucleotide variant
Location: chr11:126003951 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.62 · 3 PDB
Residue 659: the fibronectin type-iii 1 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-ser659 (accessed [today's date]).

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