Is CDKN2C p.Ala127Asp (c.380C>A) pathogenic?

CDKN2C p.Ala127Asp (c.380C>A) is classified Uncertain significance in CDKN2C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-20). AlphaMissense: likely benign (0.2362); Absent from gnomAD v4.1.

How common is CDKN2C p.Ala127Asp (c.380C>A) in the general population?

CDKN2C p.Ala127Asp (c.380C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKN2C p.Ala127Asp (c.380C>A)?

AlphaMissense predicts likely benign (score 0.2362) — an in-silico prediction, not a clinical call.

CDKN2C p.Ala127Asp

c.380C>A · VCV3831003

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2362 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2362	likely benign
REVEL	0.351	indeterminate
SaProt	LLR -6.26	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 3,898 bp · p 0.00048 · regional, not allelic
Overall
CADD	22.3	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.

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: CDKN2C
Protein: p.Ala127Asp
Coding: c.380C>A
MANE Select: NM_078626
Type: single nucleotide variant
Location: chr1:50974143 (GRCh38)
Gene constraint: LOEUF 0.94 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 92.36 · 6 PDB

Full CDKN2C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDKN2C p.Asn159= Likely benign ★★ same type
CDKN2C p.Ala161Gly Uncertain significance ★ ⚠ same type
CDKN2C p.Ala77Val Uncertain significance ★ ⚠ same type
CDKN2C p.Arg39Ser Uncertain significance ★ ⚠ same type
CDKN2C p.Asp17His Uncertain significance ★ same type
CDKN2C p.Asp17Tyr Uncertain significance ★ ⚠ same type
CDKN2C p.Asp64His Uncertain significance ★ ⚠ same type
CDKN2C p.Asp95Glu 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/cdkn2c-p-ala127asp (accessed [today's date]).

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