Is CDON p.Glu34Ala (c.101A>C) pathogenic?

CDON p.Glu34Ala (c.101A>C) is classified Conflicting classifications of pathogenicity in CDON (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-10-30). AlphaMissense: ambiguous (0.3447); Ultra-rare (popmax 0.0233%, amr); Associated with holoprosencephaly 11.

What condition is associated with CDON p.Glu34Ala (c.101A>C)?

CDON p.Glu34Ala (c.101A>C) is associated with holoprosencephaly 11 (ClinVar).

How common is CDON p.Glu34Ala (c.101A>C) in the general population?

CDON p.Glu34Ala (c.101A>C) is ultra-rare (popmax 0.0233%, amr) (gnomAD).

What do computational predictors say about CDON p.Glu34Ala (c.101A>C)?

AlphaMissense predicts ambiguous (score 0.3447) — an in-silico prediction, not a clinical call.

CDON p.Glu34Ala

c.101A>C · rs776289358 · VCV2147303

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3447 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0233%, amr)

Conditions

holoprosencephaly 11

Computational evidence

Protein change
AlphaMissense	0.3447	ambiguous
REVEL	0.321	indeterminate
SaProt	LLR -5.16	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.42 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.1	GERP 1.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 63 kb · p 0.0032 · regional, not allelic
Overall
CADD	24.5	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 0.0233% Admixed American · 14/59,972 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.00322% 52/1,613,798 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0233%	4,284
Remaining individualsnot grpmax-eligible	0.0064%	15,621
European (non-Finnish)	0.00288%	34,704

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.Glu34Ala
Coding: c.101A>C
MANE Select: NM_001378964
dbSNP: rs776289358
Type: single nucleotide variant
Location: chr11:126021496 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.62 · 3 PDB
Residue 34: the ig-like c2-type 1 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-glu34ala (accessed [today's date]).

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