Is NSD2 p.Val435Ala (c.1304T>C) pathogenic?

NSD2 p.Val435Ala (c.1304T>C) is classified Uncertain significance in NSD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-27). AlphaMissense: likely benign (0.0685); Absent from gnomAD v4.1; Associated with Rauch-Steindl syndrome.

What condition is associated with NSD2 p.Val435Ala (c.1304T>C)?

NSD2 p.Val435Ala (c.1304T>C) is associated with Rauch-Steindl syndrome (ClinVar).

How common is NSD2 p.Val435Ala (c.1304T>C) in the general population?

NSD2 p.Val435Ala (c.1304T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NSD2 p.Val435Ala (c.1304T>C)?

AlphaMissense predicts likely benign (score 0.0685) — an in-silico prediction, not a clinical call.

NSD2 p.Val435Ala

c.1304T>C · VCV4056684

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0685 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Rauch-Steindl syndrome

Computational evidence

Protein change
AlphaMissense	0.0685	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -5.58	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 0.56	GERP -0.87
Regional constraint	o/e 0.90	unconstrained · MANE · 34 kb · p 0.024 · regional, not allelic
Overall
CADD	12.76	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

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.Val435Ala
Coding: c.1304T>C
MANE Select: NM_001042424
Type: single nucleotide variant
Location: chr4:1918517 (GRCh38)
Gene constraint: LOEUF 0.139 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.22 · 24 PDB
Residue 435: the 'disordered' region

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

Disease context

Rauch-Steindl syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NSD2 p.Arg450Ter Likely pathogenic ★★ same condition
NSD2 p.Arg755Ter Pathogenic/Likely pathogenic ★★ same condition
NSD2 p.Arg935Ter Pathogenic ★★ same condition
NSD2 p.Glu1363Lys Uncertain significance ★★ ⚠ same condition
NSD2 p.Phe922Ser Uncertain significance ★★ ⚠ same condition
NSD2 p.Pro1341= Benign/Likely benign ★★ same condition
NSD2 c.2339-1G>A Likely pathogenic ★ same condition
NSD2 c.2518+1G>A 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-val435ala (accessed [today's date]).

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