Is CDKN1B p.Ala28Val (c.83C>T) pathogenic?

CDKN1B p.Ala28Val (c.83C>T) is classified Uncertain significance in CDKN1B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-12-04). AlphaMissense: ambiguous (0.5129); Very rare (popmax 0.00127%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN1B p.Ala28Val (c.83C>T)?

CDKN1B p.Ala28Val (c.83C>T) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 4 (ClinVar).

How common is CDKN1B p.Ala28Val (c.83C>T) in the general population?

CDKN1B p.Ala28Val (c.83C>T) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about CDKN1B p.Ala28Val (c.83C>T)?

AlphaMissense predicts ambiguous (score 0.5129) — an in-silico prediction, not a clinical call.

CDKN1B p.Ala28Val

c.83C>T · rs1592280774 · VCV940679

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5129 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5129	ambiguous
REVEL	0.578	indeterminate
SaProt	LLR -4.54	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 1,103 bp · p 3.6e-06 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00127% European (non-Finnish) · 15/1,180,052 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.000929% 15/1,614,204 alleles · very rare exomes 15/1,461,858 · genomes 0/152,346 · 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: CDKN1B
Protein: p.Ala28Val
Coding: c.83C>T
MANE Select: NM_004064
dbSNP: rs1592280774
Type: single nucleotide variant
Location: chr12:12717922 (GRCh38)
Gene constraint: LOEUF 0.804 · pLI 0.24 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.08 · 19 PDB
Residue 28: the 'disordered' region; an α-helix

Full CDKN1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: multiple endocrine neoplasia type 4

Similar variants

CDKN1B p.Ala28Asp Uncertain significance ★★ ⚠ same residue
CDKN1B p.Ala28Ser Uncertain significance ★ ⚠ same residue
CDKN1B p.Arg154Ter Pathogenic ★★ same condition
CDKN1B p.Arg5Ter Pathogenic/Likely pathogenic ★★ same condition
CDKN1B p.Gln104Ter Pathogenic ★★ same condition
CDKN1B p.Gln107Ter Pathogenic ★★ same condition
CDKN1B p.Gln141Ter Pathogenic ★★ same condition
CDKN1B p.Gln163Ter 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/cdkn1b-p-ala28val (accessed [today's date]).

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