Is NSD2 p.Thr1007Pro (c.3019A>C) pathogenic?

NSD2 p.Thr1007Pro (c.3019A>C) is classified Uncertain significance in NSD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-03). AlphaMissense: likely benign (0.1928); Absent from gnomAD v4.1; Associated with NSD2-related neurodevelopmental disorder.

What condition is associated with NSD2 p.Thr1007Pro (c.3019A>C)?

NSD2 p.Thr1007Pro (c.3019A>C) is associated with NSD2-related neurodevelopmental disorder (ClinVar).

How common is NSD2 p.Thr1007Pro (c.3019A>C) in the general population?

NSD2 p.Thr1007Pro (c.3019A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NSD2 p.Thr1007Pro (c.3019A>C)?

AlphaMissense predicts likely benign (score 0.1928) — an in-silico prediction, not a clinical call.

NSD2 p.Thr1007Pro

c.3019A>C · rs2108971216 · VCV1693301

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1928 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

NSD2-related neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.1928	likely benign
REVEL	0.756	pathogenic-leaning
SaProt	LLR -11.21	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.29	constrained · MANE · 20 kb · p 9e-56 · regional, not allelic
Overall
CADD	26.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NSD2
Protein: p.Thr1007Pro
Coding: c.3019A>C
MANE Select: NM_001042424
dbSNP: rs2108971216
Type: single nucleotide variant
Location: chr4:1959504 (GRCh38)
Gene constraint: LOEUF 0.139 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.22 · 24 PDB
Residue 1007: a UniProt-annotated variant site (in raust); an α-helix

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

Disease context

NSD2-related neurodevelopmental disorder

Similar variants

NSD2 p.Gly92Ser Uncertain significance ★★ ⚠ same condition
NSD2 c.761-1G>C Likely pathogenic ★ same condition
NSD2 p.Arg319Ser Likely pathogenic ★ same condition
NSD2 p.Arg944Trp Likely pathogenic ★ same condition
NSD2 p.Cys743Phe Likely pathogenic ★ same condition
NSD2 p.Cys813Tyr Likely pathogenic ★ same condition
NSD2 p.Glu123Ter Pathogenic ★ same condition
NSD2 p.Val1093Ala 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/nsd2-p-thr1007pro (accessed [today's date]).

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