Is CDON p.Pro264Gln (c.791C>A) pathogenic?

CDON p.Pro264Gln (c.791C>A) is classified Conflicting classifications of pathogenicity in CDON (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-05-05). AlphaMissense: likely benign (0.2917); Ultra-rare (popmax 0.0231%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CDON p.Pro264Gln (c.791C>A)?

CDON p.Pro264Gln (c.791C>A) is associated with Inborn genetic diseases, holoprosencephaly 11 (ClinVar).

How common is CDON p.Pro264Gln (c.791C>A) in the general population?

CDON p.Pro264Gln (c.791C>A) is ultra-rare (popmax 0.0231%, nfe) (gnomAD).

What do computational predictors say about CDON p.Pro264Gln (c.791C>A)?

AlphaMissense predicts likely benign (score 0.2917) — an in-silico prediction, not a clinical call.

CDON p.Pro264Gln

c.791C>A · rs140542787 · VCV422386

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2917 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0231%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2917	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -7.36	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 -0.31	GERP -4.1
Regional constraint	o/e 0.93	unconstrained · MANE · 63 kb · p 0.0032 · regional, not allelic
Overall
CADD	0.407	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 0.0231% European (non-Finnish) · 273/1,180,032 alleles

Filtering AF 0.0209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.02%

Overall 0.0175% 283/1,613,996 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0231%	4,322
Remaining individualsnot grpmax-eligible	0.008%	12,497
Admixed American	0.00333%	29,999
Finnishnot grpmax-eligible	0.00312%	32,010
East Asian	0.00223%	44,888

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.Pro264Gln
Coding: c.791C>A
MANE Select: NM_001378964
dbSNP: rs140542787
Type: single nucleotide variant
Location: chr11:126017225 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.62 · 3 PDB
Residue 264: a disulfide bond; the ig-like c2-type 3 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: holoprosencephaly 11

Similar variants

CDON p.Pro264Ala Uncertain significance ★ ⚠ same residue
CDON p.Pro264= Likely benign ★ 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-pro264gln (accessed [today's date]).

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