Is CDKN1C p.Pro181Arg (c.542C>G) pathogenic?

CDKN1C p.Pro181Arg (c.542C>G) is classified Uncertain significance in CDKN1C (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-17). AlphaMissense: ambiguous (0.3418); Ultra-rare (popmax 0.0169%, amr); Associated with Inborn genetic diseases.

What condition is associated with CDKN1C p.Pro181Arg (c.542C>G)?

CDKN1C p.Pro181Arg (c.542C>G) is associated with Inborn genetic diseases, Beckwith-Wiedemann syndrome, IMAGe syndrome (ClinVar).

How common is CDKN1C p.Pro181Arg (c.542C>G) in the general population?

CDKN1C p.Pro181Arg (c.542C>G) is ultra-rare (popmax 0.0169%, amr) (gnomAD).

What do computational predictors say about CDKN1C p.Pro181Arg (c.542C>G)?

AlphaMissense predicts ambiguous (score 0.3418) — an in-silico prediction, not a clinical call.

CDKN1C p.Pro181Arg

c.542C>G · rs1377428359 · VCV572297

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3418 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3418	ambiguous
REVEL	0.083	moderately benign-leaning
SaProt	LLR -12.91	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -0.78, phastCons 0.008
Overall
CADD	9.668	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 P192R vs ClinVar P181R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0169% Admixed American · 3/17,736 alleles

Filtering AF 0.00457% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.000563% 5/888,042 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0169%	5,912
South Asian	0.00512%	19,532
Remaining individualsnot grpmax-eligible	0.00352%	28,436

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.Pro181Arg
Coding: c.542C>G
MANE Select: NM_001122630
dbSNP: rs1377428359
Type: single nucleotide variant
Location: chr11:2884915 (GRCh38)
Gene constraint: LOEUF 1.943 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.93
Residue 181: the '9 x 4 aa repeats of p-a-p-a' region; the 'disordered' region; a UniProt-annotated variant site (in hepatocellular carcinomas)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Beckwith-Wiedemann syndrome IMAGe syndrome

Similar variants

CDKN1C p.Pro181Ser Uncertain significance ★ ⚠ same residue
CDKN1C p.Pro181= Likely benign ★ same residue
CDKN1C p.Pro181fs Pathogenic ★ same residue
CDKN1C p.Pro181_Ala182insSerPro 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-pro181arg (accessed [today's date]).

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