Is CDKN1C p.Pro138Ser (c.412C>T) pathogenic?

CDKN1C p.Pro138Ser (c.412C>T) is classified Uncertain significance in CDKN1C (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-31). AlphaMissense: likely benign (0.0788); Very rare (popmax 0.00409%, amr); Associated with Beckwith-Wiedemann syndrome.

What condition is associated with CDKN1C p.Pro138Ser (c.412C>T)?

CDKN1C p.Pro138Ser (c.412C>T) is associated with Beckwith-Wiedemann syndrome (ClinVar).

How common is CDKN1C p.Pro138Ser (c.412C>T) in the general population?

CDKN1C p.Pro138Ser (c.412C>T) is very rare (popmax 0.00409%, amr) (gnomAD).

What do computational predictors say about CDKN1C p.Pro138Ser (c.412C>T)?

AlphaMissense predicts likely benign (score 0.0788) — an in-silico prediction, not a clinical call.

CDKN1C p.Pro138Ser

c.412C>T · rs1590150454 · VCV647181

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0788 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00409%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Beckwith-Wiedemann syndrome

Computational evidence

Protein change
AlphaMissense	0.0788	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -10.47	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 0.29	GERP 0.5, phastCons 0.99
Overall
CADD	15.44	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 P149S vs ClinVar P138S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00409% Admixed American · 1/24,458 alleles

Filtering AF 8.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 6e-05%

Overall 0.000375% 5/1,334,304 alleles · very rare exomes 5/1,183,632 · genomes 0/150,672 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00409%	24,458
European (non-Finnish)	0.000382%	261,853

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.Pro138Ser
Coding: c.412C>T
MANE Select: NM_001122630
dbSNP: rs1590150454
Type: single nucleotide variant
Location: chr11:2885045 (GRCh38)
Gene constraint: LOEUF 1.943 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.93
Residue 149 UniProt numbering: the 'disordered' region

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

Disease context

Beckwith-Wiedemann syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDKN1C p.Pro138Leu Uncertain significance ★★ ⚠ same residue
CDKN1C p.Pro138= Likely benign ★ same residue
CDKN1C p.Asp263Asn Pathogenic ★★ ⚠ same condition
CDKN1C p.Cys19Ter Pathogenic/Likely pathogenic ★★ same condition
CDKN1C p.Gln219Ter Pathogenic ★★ same condition
CDKN1C p.Gln221Ter Pathogenic ★★ same condition
CDKN1C p.Gln230Ter Pathogenic ★★ same condition
CDKN1C p.Glu119Ter 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-pro138ser (accessed [today's date]).

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