Is CDKN2A p.Thr137fs (c.407dup) pathogenic?

CDKN2A p.Thr137fs (c.407dup) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-19). Very rare (popmax 0.004%, afr); Associated with melanoma and neural system tumor syndrome.

What condition is associated with CDKN2A p.Thr137fs (c.407dup)?

CDKN2A p.Thr137fs (c.407dup) is associated with melanoma and neural system tumor syndrome, melanoma-pancreatic cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Thr137fs (c.407dup) in the general population?

CDKN2A p.Thr137fs (c.407dup) is very rare (popmax 0.004%, afr) (gnomAD).

How is Melanoma and neural system tumor syndrome inherited?

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

CDKN2A p.Thr137fs

c.407dup · rs749588877 · VCV483327

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Conditions

melanoma and neural system tumor syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (2 of 3, 49 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.38	GERP -1.4
Overall
CADD	20.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,922 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000993% 16/1,611,782 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00962%	10,399
African / African-Americangrpmax	0.004%	24,974
Admixed American	0.00333%	30,003
South Asian	0.0022%	45,527
European (non-Finnish)	0.000254%	393,340

Finnish 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.Thr137fs
Coding: c.407dup
MANE Select: NM_000077
dbSNP: rs749588877
Type: Duplication
Location: chr9:21970951 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB

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

Disease context

melanoma and neural system tumor syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: melanoma-pancreatic cancer syndrome hereditary neoplastic syndrome familial melanoma

For Melanoma and neural system tumor syndrome (Orphanet):

Inheritance: Autosomal dominant, Unknown
Onset: Adult, Elderly

Similar variants

CDKN2A p.Thr137Ile Uncertain significance ★★ ⚠ same residue
CDKN2A p.Thr137= Likely benign ★★ same residue
CDKN2A p.Arg112_Leu113insArg Pathogenic ★★ same condition
CDKN2A p.Arg46fs Pathogenic ★★ same condition
CDKN2A p.Leu121fs Pathogenic/Likely pathogenic ★★ same condition
CDKN2A p.Leu97fs Pathogenic/Likely pathogenic ★★ same condition
CDKN2A p.Ser43Ter Pathogenic ★★ same condition
CDKN2A p.Ser8fs 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-thr137fs (accessed [today's date]).

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