Is CDKN1C p.Ala289Ser (c.865G>T) pathogenic?

CDKN1C p.Ala289Ser (c.865G>T) is classified Conflicting classifications of pathogenicity in CDKN1C (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-22). AlphaMissense: likely benign (0.0868); Ultra-rare (popmax 0.046%, sas); Associated with Inborn genetic diseases.

What condition is associated with CDKN1C p.Ala289Ser (c.865G>T)?

CDKN1C p.Ala289Ser (c.865G>T) is associated with Inborn genetic diseases, Beckwith-Wiedemann syndrome (ClinVar).

How common is CDKN1C p.Ala289Ser (c.865G>T) in the general population?

CDKN1C p.Ala289Ser (c.865G>T) is ultra-rare (popmax 0.046%, sas) (gnomAD).

What do computational predictors say about CDKN1C p.Ala289Ser (c.865G>T)?

AlphaMissense predicts likely benign (score 0.0868) — an in-silico prediction, not a clinical call.

CDKN1C p.Ala289Ser

c.865G>T · rs755160554 · VCV645470

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0868 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.046%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0868	likely benign
REVEL	0.105	moderately benign-leaning
SaProt	LLR -6.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -1.5, phastCons 0.98
Overall
CADD	13.92	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 A300S vs ClinVar A289S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.046% South Asian · 39/84,700 alleles

Filtering AF 0.0346% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0306%

Overall 0.00283% 44/1,553,344 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.046%	2,172
Middle Eastern	0.0178%	5,626
Remaining individualsnot grpmax-eligible	0.00333%	30,047
African / African-American	0.00137%	73,038
European (non-Finnish)	8.7e-05%	1,148,926

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.Ala289Ser
Coding: c.865G>T
MANE Select: NM_001122630
dbSNP: rs755160554
Type: single nucleotide variant
Location: chr11:2884057 (GRCh38)
Gene constraint: LOEUF 1.943 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.93
Residue 289: 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.Ala289= Likely benign ★ same residue
CDKN1C p.Ala289Pro 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-ala289ser (accessed [today's date]).

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