Is CDKN1C p.Ala246Asp (c.737C>A) pathogenic?

CDKN1C p.Ala246Asp (c.737C>A) is classified Uncertain significance in CDKN1C (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-08). AlphaMissense: likely pathogenic (0.7467); Very rare (popmax 8.84e-05%, nfe); Associated with Beckwith-Wiedemann syndrome.

What condition is associated with CDKN1C p.Ala246Asp (c.737C>A)?

CDKN1C p.Ala246Asp (c.737C>A) is associated with Beckwith-Wiedemann syndrome, IMAGe syndrome (ClinVar).

How common is CDKN1C p.Ala246Asp (c.737C>A) in the general population?

CDKN1C p.Ala246Asp (c.737C>A) is very rare (popmax 8.84e-05%, nfe) (gnomAD).

What do computational predictors say about CDKN1C p.Ala246Asp (c.737C>A)?

AlphaMissense predicts likely pathogenic (score 0.7467) — an in-silico prediction, not a clinical call.

CDKN1C p.Ala246Asp

c.737C>A · VCV3599528

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7467 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.84e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Beckwith-Wiedemann syndrome

Computational evidence

Protein change
AlphaMissense	0.7467	likely pathogenic
REVEL	0.201	benign-leaning
SaProt	LLR -8.31	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.59, phastCons 0.49
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A257D vs ClinVar A246D) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.84e-05% European (non-Finnish) · 1/1,131,130 alleles

Overall 7.39e-05% 1/1,353,748 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: CDKN1C
Protein: p.Ala246Asp
Coding: c.737C>A
MANE Select: NM_001122630
Type: single nucleotide variant
Location: chr11:2884720 (GRCh38)
Gene constraint: LOEUF 1.943 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.93
Residue 246: the 'disordered' region

Full CDKN1C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Beckwith-Wiedemann syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: IMAGe syndrome

Similar variants

CDKN1C p.Ala246Gly Uncertain significance ★★ ⚠ same residue
CDKN1C p.Ala246Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN1C p.Ala246= Likely benign ★ same residue
CDKN1C p.Ala246_Ala252del Uncertain significance ★★ same residue
CDKN1C p.Arg268Ser Likely pathogenic ★★ same condition
CDKN1C p.Asp263Asn Pathogenic ★★ ⚠ same condition
CDKN1C p.Cys19Ter Pathogenic/Likely pathogenic ★★ same condition
CDKN1C p.Gln219Ter Pathogenic ★★ 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/cdkn1c-p-ala246asp (accessed [today's date]).

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