Is CDKN1C p.Ala185Pro (c.553G>C) pathogenic?

CDKN1C p.Ala185Pro (c.553G>C) is classified Conflicting classifications of pathogenicity in CDKN1C (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-06). AlphaMissense: likely benign (0.0604); Ultra-rare (popmax 0.0102%, eas); Associated with IMAGe syndrome.

What condition is associated with CDKN1C p.Ala185Pro (c.553G>C)?

CDKN1C p.Ala185Pro (c.553G>C) is associated with IMAGe syndrome, Beckwith-Wiedemann syndrome (ClinVar).

How common is CDKN1C p.Ala185Pro (c.553G>C) in the general population?

CDKN1C p.Ala185Pro (c.553G>C) is ultra-rare (popmax 0.0102%, eas) (gnomAD).

What do computational predictors say about CDKN1C p.Ala185Pro (c.553G>C)?

AlphaMissense predicts likely benign (score 0.0604) — an in-silico prediction, not a clinical call.

CDKN1C p.Ala185Pro

c.553G>C · rs1281835164 · VCV524686

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0604 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

IMAGe syndrome

Computational evidence

Protein change
AlphaMissense	0.0604	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -6.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.88	GERP -0.61
Overall
CADD	0.963	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 A196P vs ClinVar A185P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0102% East Asian · 1/9,810 alleles

Filtering AF 0.000134% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000593% 5/842,694 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0102%	9,810
European (non-Finnish)	0.000574%	174,342

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.Ala185Pro
Coding: c.553G>C
MANE Select: NM_001122630
dbSNP: rs1281835164
Type: single nucleotide variant
Location: chr11:2884904 (GRCh38)
Gene constraint: LOEUF 1.943 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.93
Residue 185: the '9 x 4 aa repeats of p-a-p-a' region; the 'disordered' region

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.Ala185= Likely benign ★ same residue
CDKN1C p.Ala185Leu Uncertain significance ★★ same residue
CDKN1C p.Ala185_Ala190dup Conflicting classifications of pathogenicity ★ same residue
CDKN1C p.Ala185_Ala186insValAlaValLeuAlaPro 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

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-ala185pro (accessed [today's date]).

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