Is NSD2 p.Pro1342Ser (c.4024C>T) pathogenic?

NSD2 p.Pro1342Ser (c.4024C>T) is classified Conflicting classifications of pathogenicity in NSD2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-03-30). AlphaMissense: likely benign (0.0663); Rare (popmax 0.149%, mid); Associated with Inborn genetic diseases.

What condition is associated with NSD2 p.Pro1342Ser (c.4024C>T)?

NSD2 p.Pro1342Ser (c.4024C>T) is associated with Inborn genetic diseases (ClinVar).

How common is NSD2 p.Pro1342Ser (c.4024C>T) in the general population?

NSD2 p.Pro1342Ser (c.4024C>T) is rare (popmax 0.149%, mid) (gnomAD).

What do computational predictors say about NSD2 p.Pro1342Ser (c.4024C>T)?

AlphaMissense predicts likely benign (score 0.0663) — an in-silico prediction, not a clinical call.

NSD2 p.Pro1342Ser

c.4024C>T · rs535066596 · VCV1680229

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0663 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.149%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0663	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -5.80	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 -0.3	GERP -0.81
Regional constraint	o/e 1.40	unconstrained · MANE · 206 bp · p 0.0001 · regional, not allelic
Overall
CADD	1.009	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 0.149% Middle Eastern · 9/6,044 alleles

Filtering AF 0.0776% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.058%

Overall 0.0196% 315/1,603,596 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.149%	672
Ashkenazi Jewishnot grpmax-eligible	0.0985%	1,015
South Asian	0.0609%	1,642
Remaining individualsnot grpmax-eligible	0.0258%	3,873
Admixed American	0.0168%	5,954
European (non-Finnish)	0.0161%	6,203
East Asian	0.00674%	14,834
African / African-American	0.00401%	24,961
Finnishnot grpmax-eligible	0.00157%	63,624

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: NSD2
Protein: p.Pro1342Ser
Coding: c.4024C>T
MANE Select: NM_001042424
dbSNP: rs535066596
Type: single nucleotide variant
Location: chr4:1978835 (GRCh38)
Gene constraint: LOEUF 0.139 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.22 · 24 PDB
Residue 1342: the 'disordered' region; a UniProt-annotated variant site (in raust)

Full NSD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NSD2 p.Pro1342Arg Uncertain significance ★ ⚠ same residue
NSD2 p.Pro1342Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
NSD2 p.Pro1342His Likely benign ★ same residue
NSD2 p.Pro1342= Likely benign ★ same residue
NSD2 p.Pro895Leu Pathogenic ★★ same condition
NSD2 p.Ala320Thr Uncertain significance ★★ ⚠ same condition
NSD2 p.Ala383Gly Uncertain significance ★★ ⚠ same condition
NSD2 p.Ala693Asp Uncertain significance ★★ ⚠ 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/nsd2-p-pro1342ser (accessed [today's date]).

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