Is NSD2 p.Ser708= (c.2124C>T) pathogenic?

NSD2 p.Ser708= (c.2124C>T) is classified Uncertain significance in NSD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-25). Very rare (popmax 0.00133%, afr).

How common is NSD2 p.Ser708= (c.2124C>T) in the general population?

NSD2 p.Ser708= (c.2124C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

NSD2 p.Ser708=

c.2124C>T · rs532704104 · VCV1680189

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.40	donor gain · deltas
Pangolin	Δ0.33	loss · gain 0.32 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP -4.5	GERP -3.7
Overall
CADD	12.26	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,032 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000744% 12/1,613,758 alleles · very rare exomes 8/1,461,438 · genomes 4/152,320 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,235
African / African-Americangrpmax	0.00133%	75,032
European (non-Finnish)	0.000763%	131,107

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: NSD2
Protein: p.Ser708=
Coding: c.2124C>T
MANE Select: NM_001042424
dbSNP: rs532704104
Type: single nucleotide variant
Location: chr4:1952218 (GRCh38)
Gene constraint: LOEUF 0.139 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.22 · 24 PDB
Residue 708: a UniProt-annotated variant site (in raust)

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

Similar variants

NSD2 p.Arg450Ter Likely pathogenic ★★ same type
NSD2 p.Arg755Ter Pathogenic/Likely pathogenic ★★ same type
NSD2 p.Arg935Ter Pathogenic ★★ same type
NSD2 p.Pro895Leu Pathogenic ★★ same type
NSD2 p.Ala320Thr Uncertain significance ★★ ⚠ same type
NSD2 p.Ala383Gly Uncertain significance ★★ ⚠ same type
NSD2 p.Ala693Asp Uncertain significance ★★ ⚠ same type
NSD2 p.Ala965Thr Uncertain significance ★★ ⚠ same type

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-ser708 (accessed [today's date]).

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