Is NSD1 p.Ile2007Phe (c.6019A>T) pathogenic?

NSD1 p.Ile2007Phe (c.6019A>T) is classified Likely pathogenic in NSD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2014-10-21). AlphaMissense: likely pathogenic (0.9991); Absent from gnomAD v4.1; Associated with Sotos syndrome.

What condition is associated with NSD1 p.Ile2007Phe (c.6019A>T)?

NSD1 p.Ile2007Phe (c.6019A>T) is associated with Sotos syndrome (ClinVar).

How common is NSD1 p.Ile2007Phe (c.6019A>T) in the general population?

NSD1 p.Ile2007Phe (c.6019A>T) is absent from gnomAD v4.1 (gnomAD).

How is Sotos syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NSD1 p.Ile2007Phe (c.6019A>T)?

AlphaMissense predicts likely pathogenic (score 0.9991) — an in-silico prediction, not a clinical call.

NSD1 p.Ile2007Phe

c.6019A>T · rs1057516048 · VCV369685

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9991 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Sotos syndrome

Computational evidence

Protein change
AlphaMissense	0.9991	likely pathogenic ✓ concordant with ClinVar · top 3% in NSD1
REVEL	0.946	strongly pathogenic-leaning
SaProt	LLR -14.38	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 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.22	constrained · MANE · 9,412 bp · p 1.4e-17 · regional, not allelic
Overall
CADD	32.0	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: NSD1
Protein: p.Ile2007Phe
Coding: c.6019A>T
MANE Select: NM_022455
dbSNP: rs1057516048
Type: single nucleotide variant
Location: chr5:177283796 (GRCh38)
Gene constraint: LOEUF 0.144 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 45.26 · 4 PDB
Residue 2007: a β-strand; the set domain

Full NSD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Sotos syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Antenatal, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

NSD1 p.Ile2007Thr Pathogenic/Likely pathogenic ★★ same residue
NSD1 c.1064-2A>G Pathogenic/Likely pathogenic ★★ same condition
NSD1 c.3921+1G>A Likely pathogenic ★★ same condition
NSD1 c.4192+2T>G Pathogenic ★★ same condition
NSD1 c.4378+1G>A Pathogenic/Likely pathogenic ★★ same condition
NSD1 c.4766-2A>G Pathogenic/Likely pathogenic ★★ same condition
NSD1 c.4966+1G>A Pathogenic ★★ same condition
NSD1 c.4966+1G>C 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/nsd1-p-ile2007phe (accessed [today's date]).

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