Is NSD2 p.Pro636Arg (c.1907C>G) pathogenic?

NSD2 p.Pro636Arg (c.1907C>G) is classified Uncertain significance in NSD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-09). AlphaMissense: likely benign (0.0953); Very rare (popmax 0.00364%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NSD2 p.Pro636Arg (c.1907C>G)?

NSD2 p.Pro636Arg (c.1907C>G) is associated with Inborn genetic diseases (ClinVar).

How common is NSD2 p.Pro636Arg (c.1907C>G) in the general population?

NSD2 p.Pro636Arg (c.1907C>G) is very rare (popmax 0.00364%, nfe) (gnomAD).

What do computational predictors say about NSD2 p.Pro636Arg (c.1907C>G)?

AlphaMissense predicts likely benign (score 0.0953) — an in-silico prediction, not a clinical call.

NSD2 p.Pro636Arg

c.1907C>G · VCV3407985

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0953 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00364%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0953	likely benign
REVEL	0.322	indeterminate
SaProt	LLR -5.83	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 34 kb · p 0.024 · regional, not allelic
Overall
CADD	18.76	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

Grpmax group 0.00364% European (non-Finnish) · 43/1,180,020 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00279% 45/1,614,066 alleles · very rare exomes 42/1,461,844 · genomes 3/152,222 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00364%	27,442
Remaining individualsnot grpmax-eligible	0.0032%	31,242

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.Pro636Arg
Coding: c.1907C>G
MANE Select: NM_001042424
Type: single nucleotide variant
Location: chr4:1951097 (GRCh38)
Gene constraint: LOEUF 0.139 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.22 · 24 PDB
Residue 636: the 'disordered' region; a UniProt-annotated variant site (in raust)

Full NSD2 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

NSD2 p.Pro895Leu Pathogenic ★★ same condition
NSD2 p.Ala320Thr Uncertain significance ★★ ⚠ same condition
NSD2 p.Ala383Gly Uncertain significance ★★ ⚠ same condition
NSD2 p.Ala693Asp Uncertain significance ★★ ⚠ same condition
NSD2 p.Ala965Thr Uncertain significance ★★ ⚠ same condition
NSD2 p.Arg1355Gln Uncertain significance ★★ ⚠ same condition
NSD2 p.Asn870Ser Uncertain significance ★★ ⚠ same condition
NSD2 p.Asp1327Glu 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/nsd2-p-pro636arg (accessed [today's date]).

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