Is NSD2 p.Pro1343Ser (c.4027C>T) pathogenic?

NSD2 p.Pro1343Ser (c.4027C>T) is classified Uncertain significance in NSD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-04-04). AlphaMissense: likely benign (0.0692); Very rare (popmax 0.000682%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NSD2 p.Pro1343Ser (c.4027C>T)?

NSD2 p.Pro1343Ser (c.4027C>T) is associated with Inborn genetic diseases (ClinVar).

How common is NSD2 p.Pro1343Ser (c.4027C>T) in the general population?

NSD2 p.Pro1343Ser (c.4027C>T) is very rare (popmax 0.000682%, nfe) (gnomAD).

What do computational predictors say about NSD2 p.Pro1343Ser (c.4027C>T)?

AlphaMissense predicts likely benign (score 0.0692) — an in-silico prediction, not a clinical call.

NSD2 p.Pro1343Ser

c.4027C>T · rs142054662 · VCV2532869

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0692 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000682%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0692	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -6.07	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 0.36	GERP 0.47
Regional constraint	o/e 1.40	unconstrained · MANE · 206 bp · p 0.0001 · regional, not allelic
Overall
CADD	9.14	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000682% European (non-Finnish) · 8/1,172,402 alleles

Filtering AF 0.000294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000212%

Overall 0.000551% 8/1,451,278 alleles · very rare

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.Pro1343Ser
Coding: c.4027C>T
MANE Select: NM_001042424
dbSNP: rs142054662
Type: single nucleotide variant
Location: chr4:1978838 (GRCh38)
Gene constraint: LOEUF 0.139 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.22 · 24 PDB
Residue 1343: 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.Pro1343Leu Uncertain significance ★★ ⚠ same residue
NSD2 p.Pro1343Ala Likely benign ★★ same residue
NSD2 p.Pro1343fs Pathogenic/Likely pathogenic ★★ 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
NSD2 p.Ala965Thr 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-pro1343ser (accessed [today's date]).

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