Is CDON p.Ser463Pro (c.1387T>C) pathogenic?

CDON p.Ser463Pro (c.1387T>C) is classified Conflicting classifications of pathogenicity in CDON (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-02). AlphaMissense: likely benign (0.1851); Ultra-rare (popmax 0.0185%, nfe); Associated with holoprosencephaly 11.

What condition is associated with CDON p.Ser463Pro (c.1387T>C)?

CDON p.Ser463Pro (c.1387T>C) is associated with holoprosencephaly 11 (ClinVar).

How common is CDON p.Ser463Pro (c.1387T>C) in the general population?

CDON p.Ser463Pro (c.1387T>C) is ultra-rare (popmax 0.0185%, nfe) (gnomAD).

What do computational predictors say about CDON p.Ser463Pro (c.1387T>C)?

AlphaMissense predicts likely benign (score 0.1851) — an in-silico prediction, not a clinical call.

CDON p.Ser463Pro

c.1387T>C · rs146002530 · VCV842607

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1851 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0185%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

holoprosencephaly 11

Computational evidence

Protein change
AlphaMissense	0.1851	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -6.54	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 -0.86	GERP -2.9
Regional constraint	o/e 0.93	unconstrained · MANE · 63 kb · p 0.0032 · regional, not allelic
Overall
CADD	0.075	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 0.0185% European (non-Finnish) · 218/1,180,024 alleles

Filtering AF 0.0165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.0152% 246/1,614,160 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0185%	5,413
Remaining individualsnot grpmax-eligible	0.016%	6,251
South Asian	0.0132%	7,590
Admixed American	0.00666%	15,006
East Asian	0.00223%	44,872
Finnishnot grpmax-eligible	0.00156%	64,034

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.Ser463Pro
Coding: c.1387T>C
MANE Select: NM_001378964
dbSNP: rs146002530
Type: single nucleotide variant
Location: chr11:126010506 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.62 · 3 PDB
Residue 463: the ig-like c2-type 5 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 p.Ser463Thr Uncertain significance ★ ⚠ same residue
CDON p.Ser463= 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-ser463pro (accessed [today's date]).

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