Is CDKN1C p.Ser75= (c.225G>C) pathogenic?

CDKN1C p.Ser75= (c.225G>C) is classified Likely benign in CDKN1C (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-07). Ultra-rare (popmax 0.0163%, afr); Associated with IMAGe syndrome.

What condition is associated with CDKN1C p.Ser75= (c.225G>C)?

CDKN1C p.Ser75= (c.225G>C) is associated with IMAGe syndrome, Beckwith-Wiedemann syndrome (ClinVar).

How common is CDKN1C p.Ser75= (c.225G>C) in the general population?

CDKN1C p.Ser75= (c.225G>C) is ultra-rare (popmax 0.0163%, afr) (gnomAD).

CDKN1C p.Ser75=

c.225G>C · rs1015104953 · VCV524753

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0163%, afr)

Conditions

IMAGe syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.46	GERP -1.9, phastCons 0.013
Overall
CADD	8.469	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0163% African / African-American · 12/73,398 alleles

Filtering AF 0.00939% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00142% 22/1,551,918 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0163%	6,117
East Asian	0.0146%	6,869
European (non-Finnish)	0.000348%	287,619

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.Ser75=
Coding: c.225G>C
MANE Select: NM_001122630
dbSNP: rs1015104953
Type: single nucleotide variant
Location: chr11:2885232 (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

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

Also linked: Beckwith-Wiedemann syndrome

Similar variants

CDKN1C p.Ser75Trp Uncertain significance ★★ ⚠ same residue
CDKN1C p.Ser75Ter Pathogenic ★ same residue
CDKN1C p.Ser75Ala Uncertain significance ★ ⚠ same residue
CDKN1C p.Ser75Leu Uncertain significance ★ ⚠ same residue
CDKN1C p.Ser75Pro Uncertain significance ★ ⚠ same residue
CDKN1C p.Ser75Thr Uncertain significance ★ ⚠ same residue
CDKN1C p.Arg268Ser Likely pathogenic ★★ ⚠ same condition
CDKN1C p.Asp263Asn 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-ser75 (accessed [today's date]).

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