Is CDKN2A p.Ala143Thr (c.427G>A) pathogenic?

CDKN2A p.Ala143Thr (c.427G>A) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-01-12). AlphaMissense: likely benign (0.0847); Very rare (popmax 0.00127%, nfe); Associated with familial melanoma.

What condition is associated with CDKN2A p.Ala143Thr (c.427G>A)?

CDKN2A p.Ala143Thr (c.427G>A) is associated with familial melanoma, melanoma-pancreatic cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Ala143Thr (c.427G>A) in the general population?

CDKN2A p.Ala143Thr (c.427G>A) is very rare (popmax 0.00127%, nfe) (gnomAD).

How is Familial melanoma inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDKN2A p.Ala143Thr (c.427G>A)?

AlphaMissense predicts likely benign (score 0.0847) — an in-silico prediction, not a clinical call.

CDKN2A p.Ala143Thr

c.427G>A · rs754195015 · VCV245681

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0847 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.0847	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -7.07	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 -3.1	GERP -1.9
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	2.926	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) · 15/1,180,032 alleles

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

Overall 0.0011% 16/1,460,132 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,438
European (non-Finnish)grpmax	0.00127%	78,669

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CDKN2A
Protein: p.Ala143Thr
Coding: c.427G>A
MANE Select: NM_000077
dbSNP: rs754195015
Type: single nucleotide variant
Location: chr9:21970932 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 143: a turn

Full CDKN2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial melanoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: melanoma-pancreatic cancer syndrome hereditary neoplastic syndrome

For Familial melanoma (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CDKN2A p.Ala143Gly Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala143Val Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala143= Likely benign ★★ same residue
CDKN2A p.Ala143Ser Uncertain significance ★ ⚠ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same condition
CDKN2A c.150+2T>G Likely pathogenic ★★ same condition
CDKN2A c.151-1G>A Pathogenic ★★ same condition
CDKN2A c.151-1G>C 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/cdkn2a-p-ala143thr (accessed [today's date]).

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