Is CDKN2B p.Asn41Ser (c.122A>G) pathogenic?

CDKN2B p.Asn41Ser (c.122A>G) is classified Conflicting classifications of pathogenicity in CDKN2B (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-04). AlphaMissense: likely benign (0.1559); Ultra-rare (popmax 0.0238%, nfe).

How common is CDKN2B p.Asn41Ser (c.122A>G) in the general population?

CDKN2B p.Asn41Ser (c.122A>G) is ultra-rare (popmax 0.0238%, nfe) (gnomAD).

What do computational predictors say about CDKN2B p.Asn41Ser (c.122A>G)?

AlphaMissense predicts likely benign (score 0.1559) — an in-silico prediction, not a clinical call.

CDKN2B p.Asn41Ser

c.122A>G · rs375443156 · VCV2205664

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1559 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0238%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1559	likely benign
REVEL	0.3	indeterminate
SaProt	LLR -9.90	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 2.1, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 2,963 bp · p 0.034 · regional, not allelic
Overall
CADD	24.8	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 0.0238% European (non-Finnish) · 280/1,177,832 alleles

Filtering AF 0.0214% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0206%

Overall 0.0199% 320/1,608,630 alleles · ultra-rare exomes 300/1,456,430 · genomes 20/152,200 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0352%	2,843
Remaining individualsnot grpmax-eligible	0.0241%	4,147
European (non-Finnish)grpmax	0.0238%	4,207
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,470
Admixed American	0.00168%	59,348
African / African-American	0.00134%	74,828

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: CDKN2B
Protein: p.Asn41Ser
Coding: c.122A>G
MANE Select: NM_004936
dbSNP: rs375443156
Type: single nucleotide variant
Location: chr9:22008832 (GRCh38)
Gene constraint: LOEUF 1.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.12

Full CDKN2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDKN2B p.Asn41Asp Uncertain significance ★ ⚠ same residue
CDKN2B c.157-102G>A Benign ★★ same type
CDKN2B c.157-27C>A Benign ★★ same type
CDKN2B p.Ala120= Benign ★★ same type
CDKN2B p.Leu115= Likely benign ★★ same type
CDKN2B p.Ala129Gly Uncertain significance ★ ⚠ same type
CDKN2B p.Ala129Val Uncertain significance ★ ⚠ same type
CDKN2B p.Ala23Val 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/cdkn2b-p-asn41ser (accessed [today's date]).

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