Is CDKN1C p.Pro129Arg (c.386C>G) pathogenic?

CDKN1C p.Pro129Arg (c.386C>G) is classified Uncertain significance in CDKN1C (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-23). AlphaMissense: likely benign (0.1432); Very rare (popmax 9.31e-05%, nfe).

How common is CDKN1C p.Pro129Arg (c.386C>G) in the general population?

CDKN1C p.Pro129Arg (c.386C>G) is very rare (popmax 9.31e-05%, nfe) (gnomAD).

What do computational predictors say about CDKN1C p.Pro129Arg (c.386C>G)?

AlphaMissense predicts likely benign (score 0.1432) — an in-silico prediction, not a clinical call.

CDKN1C p.Pro129Arg

c.386C>G · VCV3766237

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1432 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.31e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1432	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -10.92	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 0.53	GERP -0.63, phastCons 0.87
Overall
CADD	17.8	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 P140R vs ClinVar P129R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.31e-05% European (non-Finnish) · 1/1,073,858 alleles

Overall 7.27e-05% 1/1,375,296 alleles · very rare exomes 1/1,223,388 · genomes 0/151,908 · joint denominator

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.Pro129Arg
Coding: c.386C>G
MANE Select: NM_001122630
Type: single nucleotide variant
Location: chr11:2885071 (GRCh38)
Gene constraint: LOEUF 1.943 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.93
Residue 140 UniProt numbering: the 'disordered' region

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

Similar variants

CDKN1C p.Pro129Ser Uncertain significance ★★ ⚠ same residue
CDKN1C p.Pro129Leu Uncertain significance ★ ⚠ same residue
CDKN1C p.Pro129= Likely benign ★ 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-pro129arg (accessed [today's date]).

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