Is CDKN1C p.Val154Ala (c.461T>C) pathogenic?

CDKN1C p.Val154Ala (c.461T>C) is classified Uncertain significance in CDKN1C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-23). AlphaMissense: likely benign (0.0933); Very rare (popmax 0.00397%, afr); Associated with Beckwith-Wiedemann syndrome.

What condition is associated with CDKN1C p.Val154Ala (c.461T>C)?

CDKN1C p.Val154Ala (c.461T>C) is associated with Beckwith-Wiedemann syndrome (ClinVar).

How common is CDKN1C p.Val154Ala (c.461T>C) in the general population?

CDKN1C p.Val154Ala (c.461T>C) is very rare (popmax 0.00397%, afr) (gnomAD).

What do computational predictors say about CDKN1C p.Val154Ala (c.461T>C)?

AlphaMissense predicts likely benign (score 0.0933) — an in-silico prediction, not a clinical call.

CDKN1C p.Val154Ala

c.461T>C · rs1191295512 · VCV1397076

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0933 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00397%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Beckwith-Wiedemann syndrome

Computational evidence

Protein change
AlphaMissense	0.0933	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -9.03	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 -0.82	GERP -0.56
Overall
CADD	7.285	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V165A vs ClinVar V154A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00397% African / African-American · 2/50,320 alleles

Filtering AF 0.000659% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000247%

Overall 0.000245% 2/815,752 alleles · very rare exomes 0/706,896 · genomes 2/108,856 · 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.Val154Ala
Coding: c.461T>C
MANE Select: NM_001122630
dbSNP: rs1191295512
Type: single nucleotide variant
Location: chr11:2884996 (GRCh38)
Gene constraint: LOEUF 1.943 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.93
Residue 165 UniProt numbering: the '9 x 4 aa repeats of p-a-p-a' 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.Val154Ile Uncertain significance ★ ⚠ same residue
CDKN1C p.Val154= Likely benign ★ same residue
CDKN1C p.Val154_Ala155del Likely benign ★★ same residue
CDKN1C p.Val154_Ala155delinsAlaPro Likely benign ★ same residue
CDKN1C p.Val154_Pro173del Likely benign ★ same residue
CDKN1C p.Val154_Pro175del Likely benign ★ same residue
CDKN1C p.Val154_Pro177del Likely benign ★ same residue
CDKN1C p.Val154_Pro179del Likely benign ★ same residue

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-val154ala (accessed [today's date]).

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