Is CDKN1C p.Ala246Ser (c.736G>T) pathogenic?

CDKN1C p.Ala246Ser (c.736G>T) is classified Conflicting classifications of pathogenicity in CDKN1C (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-21). AlphaMissense: likely benign (0.1267); Ultra-rare (popmax 0.0275%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CDKN1C p.Ala246Ser (c.736G>T)?

CDKN1C p.Ala246Ser (c.736G>T) is associated with Inborn genetic diseases, Beckwith-Wiedemann syndrome, IMAGe syndrome (ClinVar).

How common is CDKN1C p.Ala246Ser (c.736G>T) in the general population?

CDKN1C p.Ala246Ser (c.736G>T) is ultra-rare (popmax 0.0275%, nfe) (gnomAD).

What do computational predictors say about CDKN1C p.Ala246Ser (c.736G>T)?

AlphaMissense predicts likely benign (score 0.1267) — an in-silico prediction, not a clinical call.

CDKN1C p.Ala246Ser

c.736G>T · rs754283907 · VCV454031

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1267 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0275%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1267	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -6.88	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 1.5	GERP 0.59, phastCons 0.19
Overall
CADD	20.7	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 A257S vs ClinVar A246S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0275% European (non-Finnish) · 311/1,130,610 alleles

Filtering AF 0.025% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0239%

Overall 0.0215% 324/1,503,614 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0275%	3,635
African / African-American	0.0117%	8,565
Remaining individualsnot grpmax-eligible	0.00877%	11,402

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.Ala246Ser
Coding: c.736G>T
MANE Select: NM_001122630
dbSNP: rs754283907
Type: single nucleotide variant
Location: chr11:2884721 (GRCh38)
Gene constraint: LOEUF 1.943 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.93
Residue 246: 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 IMAGe syndrome

Similar variants

CDKN1C p.Ala246Gly Uncertain significance ★★ ⚠ same residue
CDKN1C p.Ala246Asp Uncertain significance ★ ⚠ same residue
CDKN1C p.Ala246= Likely benign ★ same residue
CDKN1C p.Ala246_Ala252del Uncertain significance ★★ same residue
CDKN1C p.Arg268Ser Likely pathogenic ★★ same condition
CDKN1C p.Asp263Asn Pathogenic ★★ ⚠ same condition
CDKN1C p.Cys19Ter Pathogenic/Likely pathogenic ★★ same condition
CDKN1C p.Gln219Ter 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-ala246ser (accessed [today's date]).

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