Is CDKN1C p.Pro173Leu (c.518C>T) pathogenic?

CDKN1C p.Pro173Leu (c.518C>T) is classified Uncertain significance in CDKN1C (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-30). AlphaMissense: likely benign (0.1236); Very rare (popmax 0.00355%, afr); Associated with Beckwith-Wiedemann syndrome.

What condition is associated with CDKN1C p.Pro173Leu (c.518C>T)?

CDKN1C p.Pro173Leu (c.518C>T) is associated with Beckwith-Wiedemann syndrome (ClinVar).

How common is CDKN1C p.Pro173Leu (c.518C>T) in the general population?

CDKN1C p.Pro173Leu (c.518C>T) is very rare (popmax 0.00355%, afr) (gnomAD).

What do computational predictors say about CDKN1C p.Pro173Leu (c.518C>T)?

AlphaMissense predicts likely benign (score 0.1236) — an in-silico prediction, not a clinical call.

CDKN1C p.Pro173Leu

c.518C>T · rs1050598447 · VCV1394706

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1236 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00355%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Beckwith-Wiedemann syndrome

Computational evidence

Protein change
AlphaMissense	0.1236	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -10.53	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 0.037	GERP -0.88
Overall
CADD	14.43	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 P184L vs ClinVar P173L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00355% African / African-American · 2/56,372 alleles

Filtering AF 0.000588% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00022%

Overall 0.000626% 6/959,034 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00355%	28,186
European (non-Finnish)	0.000519%	192,552

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.Pro173Leu
Coding: c.518C>T
MANE Select: NM_001122630
dbSNP: rs1050598447
Type: single nucleotide variant
Location: chr11:2884939 (GRCh38)
Gene constraint: LOEUF 1.943 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.93
Residue 173: the '9 x 4 aa repeats of p-a-p-a' region; a UniProt-annotated variant site (in several cancers)

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.Pro173= 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
CDKN1C p.Glu214Ter 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-pro173leu (accessed [today's date]).

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