Is CDKN1C p.Pro59Gln (c.176C>A) pathogenic?

CDKN1C p.Pro59Gln (c.176C>A) is classified Uncertain significance in CDKN1C (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-17). AlphaMissense: likely pathogenic (0.9936); Very rare (popmax 8.56e-05%, nfe).

How common is CDKN1C p.Pro59Gln (c.176C>A) in the general population?

CDKN1C p.Pro59Gln (c.176C>A) is very rare (popmax 8.56e-05%, nfe) (gnomAD).

What do computational predictors say about CDKN1C p.Pro59Gln (c.176C>A)?

AlphaMissense predicts likely pathogenic (score 0.9936) — an in-silico prediction, not a clinical call.

CDKN1C p.Pro59Gln

c.176C>A · VCV3765648

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9936 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.56e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9936	likely pathogenic · top 4% in CDKN1C
REVEL	0.897	moderately pathogenic-leaning
SaProt	LLR -14.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.1, phastCons 1
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P70Q vs ClinVar P59Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.56e-05% European (non-Finnish) · 1/1,168,218 alleles

Overall 0.000657% 1/152,200 alleles · very rare

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.Pro59Gln
Coding: c.176C>A
MANE Select: NM_001122630
Type: single nucleotide variant
Location: chr11:2885281 (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

Similar variants

CDKN1C p.Pro59Leu Pathogenic/Likely pathogenic ★★ same residue
CDKN1C p.Pro59= Likely benign ★ same residue
CDKN1C p.Pro59fs Pathogenic ★ same residue
CDKN1C p.Arg268Ser Likely pathogenic ★★ ⚠ same type
CDKN1C p.Asp263Asn Pathogenic ★★ ⚠ same type
CDKN1C p.Cys19Ter Pathogenic/Likely pathogenic ★★ same type
CDKN1C p.Gln219Ter Pathogenic ★★ same type
CDKN1C p.Gln221Ter Pathogenic ★★ same type

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-pro59gln (accessed [today's date]).

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