Is CDKN1C p.Pro193Ala (c.577C>G) pathogenic?

CDKN1C p.Pro193Ala (c.577C>G) is classified Conflicting classifications of pathogenicity in CDKN1C (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-08). AlphaMissense: likely benign (0.0641); Ultra-rare (popmax 0.0494%, sas); Associated with Inborn genetic diseases.

What condition is associated with CDKN1C p.Pro193Ala (c.577C>G)?

CDKN1C p.Pro193Ala (c.577C>G) is associated with Inborn genetic diseases, Beckwith-Wiedemann syndrome (ClinVar).

How common is CDKN1C p.Pro193Ala (c.577C>G) in the general population?

CDKN1C p.Pro193Ala (c.577C>G) is ultra-rare (popmax 0.0494%, sas) (gnomAD).

What do computational predictors say about CDKN1C p.Pro193Ala (c.577C>G)?

AlphaMissense predicts likely benign (score 0.0641) — an in-silico prediction, not a clinical call.

CDKN1C p.Pro193Ala

c.577C>G · rs1345683292 · VCV580594

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0641 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0641	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -11.79	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9	GERP -0.71
Overall
CADD	0.811	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 P204A vs ClinVar P193A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0494% South Asian · 10/20,244 alleles

Filtering AF 0.0267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0203%

Overall 0.00443% 41/925,274 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0494%	2,024
European (non-Finnish)	0.00379%	26,419
Remaining individualsnot grpmax-eligible	0.00345%	28,966
African / African-American	0.00185%	54,110

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.Pro193Ala
Coding: c.577C>G
MANE Select: NM_001122630
dbSNP: rs1345683292
Type: single nucleotide variant
Location: chr11:2884880 (GRCh38)
Gene constraint: LOEUF 1.943 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.93
Residue 193: 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

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

Also linked: Beckwith-Wiedemann syndrome

Similar variants

CDKN1C p.Pro193Leu Uncertain significance ★★ ⚠ same residue
CDKN1C p.Pro193Arg Uncertain significance ★ ⚠ same residue
CDKN1C p.Pro193Gln Uncertain significance ★ ⚠ same residue
CDKN1C p.Pro193= Likely benign ★ same residue
CDKN1C p.Pro193fs Pathogenic ★ same residue
CDKN1C p.Pro193_Ala194insValAla Uncertain significance ★ same residue
CDKN1C p.Pro193Ser Uncertain significance ★ same residue
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-pro193ala (accessed [today's date]).

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