Is CDON p.Pro689Ala (c.2065C>G) pathogenic?

CDON p.Pro689Ala (c.2065C>G) is classified Likely pathogenic in CDON (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-04). AlphaMissense: likely benign (0.0856); Very rare (popmax 0.00333%, amr); Associated with holoprosencephaly 11.

What condition is associated with CDON p.Pro689Ala (c.2065C>G)?

CDON p.Pro689Ala (c.2065C>G) is associated with holoprosencephaly 11 (ClinVar).

How common is CDON p.Pro689Ala (c.2065C>G) in the general population?

CDON p.Pro689Ala (c.2065C>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CDON p.Pro689Ala (c.2065C>G)?

AlphaMissense predicts likely benign (score 0.0856) — an in-silico prediction, not a clinical call.

CDON p.Pro689Ala

c.2065C>G · rs387906995 · VCV30747

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0856 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

holoprosencephaly 11

Computational evidence

Protein change
AlphaMissense	0.0856	likely benign ⚠ discordant with ClinVar
REVEL	0.219	benign-leaning
SaProt	LLR -6.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP -0.072, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 63 kb · p 0.0032 · regional, not allelic
Overall
CADD	20.6	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 · 2/59,994 alleles

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

Overall 0.00031% 5/1,610,706 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,997
Remaining individualsnot grpmax-eligible	0.0016%	62,386
European (non-Finnish)	0.00017%	588,474

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.Pro689Ala
Coding: c.2065C>G
MANE Select: NM_001378964
dbSNP: rs387906995
Type: single nucleotide variant
Location: chr11:126001812 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.62 · 3 PDB
Residue 689: a UniProt-annotated variant site (in hpe11)

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 p.Pro689Ser Uncertain significance ★ ⚠ same residue
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

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-pro689ala (accessed [today's date]).

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