Is CDKN1A p.Trp49Ser (c.146G>C) pathogenic?

CDKN1A p.Trp49Ser (c.146G>C) is classified Uncertain significance in CDKN1A (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9921); Absent from gnomAD v4.1.

How common is CDKN1A p.Trp49Ser (c.146G>C) in the general population?

CDKN1A p.Trp49Ser (c.146G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKN1A p.Trp49Ser (c.146G>C)?

AlphaMissense predicts likely pathogenic (score 0.9921) — an in-silico prediction, not a clinical call.

CDKN1A p.Trp49Ser

c.146G>C · rs1260849045 · VCV1677300

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9921 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9921	likely pathogenic · top 1% in CDKN1A
REVEL	0.857	moderately pathogenic-leaning
SaProt	LLR -13.21	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,695 bp · p 0.06 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDKN1A
Protein: p.Trp49Ser
Coding: c.146G>C
MANE Select: NM_000389
dbSNP: rs1260849045
Type: single nucleotide variant
Location: chr6:36684247 (GRCh38)
Gene constraint: LOEUF 1.492 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.16 · 13 PDB
Residue 49: a β-strand

Full CDKN1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDKN1A p.Arg84Gln Likely benign ★★ ⚠ same type
CDKN1A p.Pro4= Benign/Likely benign ★★ same type
CDKN1A p.Ser31= Likely benign ★★ same type
CDKN1A p.Thr80= Likely benign ★★ same type
CDKN1A p.Ala106Val Uncertain significance ★ ⚠ same type
CDKN1A p.Arg20His Uncertain significance ★ ⚠ same type
CDKN1A p.Arg32His Uncertain significance ★ ⚠ same type
CDKN1A p.Arg46His Uncertain significance ★ ⚠ same type

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/cdkn1a-p-trp49ser (accessed [today's date]).

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