Is CDKN2A p.Ala127Ser (c.379G>T) pathogenic?

CDKN2A p.Ala127Ser (c.379G>T) is classified Benign/Likely benign in CDKN2A (ClinVar, Multiple submitters, 22 submitters; last evaluated 2026-03-30). AlphaMissense: likely benign (0.1514); Low-frequency (popmax 1.67%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Ala127Ser (c.379G>T)?

CDKN2A p.Ala127Ser (c.379G>T) is associated with hereditary neoplastic syndrome, melanoma, cutaneous malignant, susceptibility to, 2, melanoma and neural system tumor syndrome (ClinVar).

How common is CDKN2A p.Ala127Ser (c.379G>T) in the general population?

CDKN2A p.Ala127Ser (c.379G>T) is low-frequency (popmax 1.67%, afr) (gnomAD).

What do computational predictors say about CDKN2A p.Ala127Ser (c.379G>T)?

AlphaMissense predicts likely benign (score 0.1514) — an in-silico prediction, not a clinical call.

CDKN2A p.Ala127Ser

c.379G>T · rs6413464 · VCV41578

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 22 submitters

AlphaMissense

likely benign

0.1514 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.67%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1514	likely benign
REVEL	0.395	indeterminate
SaProt	LLR -9.98	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 -0.11	GERP 1.1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	14.64	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 1.67% African / African-American · 1,254/75,048 alleles

Filtering AF 1.59% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.56%

Overall 0.0951% 1,532/1,610,798 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.67%	60
Admixed American	0.228%	438
Remaining individualsnot grpmax-eligible	0.128%	780
Middle Eastern	0.0727%	1,376
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,797
European (non-Finnish)	0.00458%	21,852
South Asian	0.0011%	91,034

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.Ala127Ser
Coding: c.379G>T
MANE Select: NM_000077
dbSNP: rs6413464
Type: single nucleotide variant
Location: chr9:21970980 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 127: a UniProt-annotated variant site (in squamous cell carcinoma); an α-helix; the 'disordered' region

Full CDKN2A 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: melanoma, cutaneous malignant, susceptibility to, 2 melanoma and neural system tumor syndrome melanoma-pancreatic cancer syndrome familial melanoma

Similar variants

CDKN2A p.Ala127Val Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala127Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Ala127= Likely benign ★ 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
CDKN2A c.151-1G>T Pathogenic/Likely 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-ala127ser (accessed [today's date]).

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