Is NSD1 p.Pro228= (c.684A>G) pathogenic?

NSD1 p.Pro228= (c.684A>G) is classified Benign/Likely benign in NSD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-19). Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with NSD1 p.Pro228= (c.684A>G)?

NSD1 p.Pro228= (c.684A>G) is associated with Inborn genetic diseases (ClinVar).

How common is NSD1 p.Pro228= (c.684A>G) in the general population?

NSD1 p.Pro228= (c.684A>G) is very rare (popmax 0.00534%, afr) (gnomAD).

NSD1 p.Pro228=

c.684A>G · rs1057522319 · VCV385753

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.38	GERP -5.1, phastCons 0.62
Overall
CADD	7.906	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,912 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000558% 9/1,612,576 alleles · very rare exomes 6/1,460,350 · genomes 3/152,226 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,728
Remaining individualsnot grpmax-eligible	0.0016%	62,436
European (non-Finnish)	0.000339%	294,681

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: NSD1
Protein: p.Pro228=
Coding: c.684A>G
MANE Select: NM_022455
dbSNP: rs1057522319
Type: single nucleotide variant
Location: chr5:177135787 (GRCh38)
Gene constraint: LOEUF 0.144 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 45.26 · 4 PDB
Residue 228: the 'disordered' region

Full NSD1 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

NSD1 p.Pro228Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
NSD1 c.5622+1G>A Pathogenic/Likely pathogenic ★★ same condition
NSD1 p.Trp1709Ter Pathogenic ★★ same condition
NSD1 p.Ala1850Val Uncertain significance ★★ ⚠ same condition
NSD1 p.Ala2300Val Uncertain significance ★★ ⚠ same condition
NSD1 p.Ala2630Asp Uncertain significance ★★ ⚠ same condition
NSD1 p.Arg106Lys Uncertain significance ★★ ⚠ same condition
NSD1 p.Arg1587His 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/nsd1-p-pro228 (accessed [today's date]).

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