Is CDKN1C p.Ser75Pro (c.223T>C) pathogenic?

CDKN1C p.Ser75Pro (c.223T>C) is classified Uncertain significance in CDKN1C (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-26). AlphaMissense: likely pathogenic (0.9797); Absent from gnomAD v4.1; Associated with Beckwith-Wiedemann syndrome.

What condition is associated with CDKN1C p.Ser75Pro (c.223T>C)?

CDKN1C p.Ser75Pro (c.223T>C) is associated with Beckwith-Wiedemann syndrome (ClinVar).

How common is CDKN1C p.Ser75Pro (c.223T>C) in the general population?

CDKN1C p.Ser75Pro (c.223T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKN1C p.Ser75Pro (c.223T>C)?

AlphaMissense predicts likely pathogenic (score 0.9797) — an in-silico prediction, not a clinical call.

CDKN1C p.Ser75Pro

c.223T>C · VCV3682793

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9797 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Beckwith-Wiedemann syndrome

Computational evidence

Protein change
AlphaMissense	0.9797	likely pathogenic · top 7% in CDKN1C
REVEL	0.377	indeterminate
SaProt	LLR -8.34	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 4.8	GERP -1.2, phastCons 1
Overall
CADD	24.0	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 S86P vs ClinVar S75P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDKN1C
Protein: p.Ser75Pro
Coding: c.223T>C
MANE Select: NM_001122630
Type: single nucleotide variant
Location: chr11:2885234 (GRCh38)
Gene constraint: LOEUF 1.943 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.93

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

Similar variants

CDKN1C p.Ser75Trp Uncertain significance ★★ ⚠ same residue
CDKN1C p.Ser75= Likely benign ★★ same residue
CDKN1C p.Ser75Ter Pathogenic ★ same residue
CDKN1C p.Ser75Ala Uncertain significance ★ ⚠ same residue
CDKN1C p.Ser75Leu Uncertain significance ★ ⚠ same residue
CDKN1C p.Ser75Thr Uncertain significance ★ ⚠ same residue
CDKN1C p.Asp263Asn Pathogenic ★★ ⚠ same condition
CDKN1C p.Cys19Ter Pathogenic/Likely 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-ser75pro (accessed [today's date]).

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