Is NSD2 p.Val1093Phe (c.3277G>T) pathogenic?

NSD2 p.Val1093Phe (c.3277G>T) is classified Likely pathogenic in NSD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-31). AlphaMissense: likely pathogenic (0.9826); Absent from gnomAD v4.1; Associated with Rauch-Steindl syndrome.

What condition is associated with NSD2 p.Val1093Phe (c.3277G>T)?

NSD2 p.Val1093Phe (c.3277G>T) is associated with Rauch-Steindl syndrome (ClinVar).

How common is NSD2 p.Val1093Phe (c.3277G>T) in the general population?

NSD2 p.Val1093Phe (c.3277G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NSD2 p.Val1093Phe (c.3277G>T)?

AlphaMissense predicts likely pathogenic (score 0.9826) — an in-silico prediction, not a clinical call.

NSD2 p.Val1093Phe

c.3277G>T · rs1440755101 · VCV2692316

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9826 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Rauch-Steindl syndrome

Computational evidence

Protein change
AlphaMissense	0.9826	likely pathogenic ✓ concordant with ClinVar
REVEL	0.753	pathogenic-leaning
SaProt	LLR -14.54	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.29	constrained · MANE · 20 kb · p 9e-56 · regional, not allelic
Overall
CADD	29.3	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.Val1093Phe
Coding: c.3277G>T
MANE Select: NM_001042424
dbSNP: rs1440755101
Type: single nucleotide variant
Location: chr4:1961056 (GRCh38)
Gene constraint: LOEUF 0.139 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.22 · 24 PDB
Residue 1093: the set domain; a UniProt-annotated variant site (in raust)

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.Val1093Ala Likely pathogenic ★ same residue
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.Val435Ala Uncertain significance ★★ ⚠ same condition
NSD2 p.Pro1341= Benign/Likely benign ★★ 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-val1093phe (accessed [today's date]).

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