Is CDON p.Pro351Ala (c.1051C>G) pathogenic?

CDON p.Pro351Ala (c.1051C>G) is classified Benign/Likely benign in CDON (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1056); Low-frequency (popmax 4.96%, afr); Associated with holoprosencephaly 11.

What condition is associated with CDON p.Pro351Ala (c.1051C>G)?

CDON p.Pro351Ala (c.1051C>G) is associated with holoprosencephaly 11 (ClinVar).

How common is CDON p.Pro351Ala (c.1051C>G) in the general population?

CDON p.Pro351Ala (c.1051C>G) is low-frequency (popmax 4.96%, afr) (gnomAD).

What do computational predictors say about CDON p.Pro351Ala (c.1051C>G)?

AlphaMissense predicts likely benign (score 0.1056) — an in-silico prediction, not a clinical call.

CDON p.Pro351Ala

c.1051C>G · rs35665264 · VCV260781

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1056 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.96%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

holoprosencephaly 11

Computational evidence

Protein change
AlphaMissense	0.1056	likely benign
REVEL	0.458	indeterminate
SaProt	LLR -6.17	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 63 kb · p 0.0032 · regional, not allelic
Overall
CADD	23.3	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 4.96% African / African-American · 3,724/75,008 alleles

Filtering AF 4.83% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.78%

Overall 0.278% 4,482/1,614,146 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.96%	20
Admixed American	0.408%	245
Remaining individualsnot grpmax-eligible	0.328%	305
Middle Eastern	0.247%	404
European (non-Finnish)	0.0242%	4,140
South Asian	0.00769%	13,011
Finnishnot grpmax-eligible	0.00156%	64,038

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.Pro351Ala
Coding: c.1051C>G
MANE Select: NM_001378964
dbSNP: rs35665264
Type: single nucleotide variant
Location: chr11:126015388 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.62 · 3 PDB
Residue 351: a disulfide bond; a UniProt-annotated variant site (in); the ig-like c2-type 4 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-pro351ala (accessed [today's date]).

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