Is CDON p.Pro3Ser (c.7C>T) pathogenic?

CDON p.Pro3Ser (c.7C>T) is classified Conflicting classifications of pathogenicity in CDON (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-12). AlphaMissense: likely benign (0.1738); Very rare (popmax 0.00221%, nfe); Associated with holoprosencephaly 11.

What condition is associated with CDON p.Pro3Ser (c.7C>T)?

CDON p.Pro3Ser (c.7C>T) is associated with holoprosencephaly 11 (ClinVar).

How common is CDON p.Pro3Ser (c.7C>T) in the general population?

CDON p.Pro3Ser (c.7C>T) is very rare (popmax 0.00221%, nfe) (gnomAD).

What do computational predictors say about CDON p.Pro3Ser (c.7C>T)?

AlphaMissense predicts likely benign (score 0.1738) — an in-silico prediction, not a clinical call.

CDON p.Pro3Ser

c.7C>T · rs771518021 · VCV930547

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1738 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00221%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

holoprosencephaly 11

Computational evidence

Protein change
AlphaMissense	0.1738	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -5.61	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 8.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 63 kb · p 0.0032 · regional, not allelic
Overall
CADD	16.61	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 0.00221% European (non-Finnish) · 26/1,177,120 alleles

Filtering AF 0.00154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00161% 26/1,610,754 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.Pro3Ser
Coding: c.7C>T
MANE Select: NM_001378964
dbSNP: rs771518021
Type: single nucleotide variant
Location: chr11:126023470 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.62 · 3 PDB

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.Pro3= Benign ★★ same residue
CDON p.Pro3Leu 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

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-pro3ser (accessed [today's date]).

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