Is CDKN1C p.Pro259Thr (c.775C>A) pathogenic?

CDKN1C p.Pro259Thr (c.775C>A) is classified Uncertain significance in CDKN1C (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-23). AlphaMissense: likely pathogenic (0.7826); Very rare (popmax 9.05e-05%, nfe); Associated with Beckwith-Wiedemann syndrome.

What condition is associated with CDKN1C p.Pro259Thr (c.775C>A)?

CDKN1C p.Pro259Thr (c.775C>A) is associated with Beckwith-Wiedemann syndrome, IMAGe syndrome (ClinVar).

How common is CDKN1C p.Pro259Thr (c.775C>A) in the general population?

CDKN1C p.Pro259Thr (c.775C>A) is very rare (popmax 9.05e-05%, nfe) (gnomAD).

What do computational predictors say about CDKN1C p.Pro259Thr (c.775C>A)?

AlphaMissense predicts likely pathogenic (score 0.7826) — an in-silico prediction, not a clinical call.

CDKN1C p.Pro259Thr

c.775C>A · rs1416211722 · VCV454033

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7826 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.05e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Beckwith-Wiedemann syndrome

Computational evidence

Protein change
AlphaMissense	0.7826	likely pathogenic
REVEL	0.34	indeterminate
SaProt	LLR -6.00	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 0.59, phastCons 1
Overall
CADD	23.7	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 P270T vs ClinVar P259T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.05e-05% European (non-Finnish) · 1/1,105,506 alleles

Overall 7.65e-05% 1/1,306,866 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.Pro259Thr
Coding: c.775C>A
MANE Select: NM_001122630
dbSNP: rs1416211722
Type: single nucleotide variant
Location: chr11:2884682 (GRCh38)
Gene constraint: LOEUF 1.943 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.93
Residue 259: 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.Pro259Ala Uncertain significance ★ ⚠ same residue
CDKN1C p.Pro259Ser Uncertain significance ★ ⚠ same residue
CDKN1C p.Pro259= Likely benign ★ 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
CDKN1C p.Gln221Ter 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-pro259thr (accessed [today's date]).

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