# NM_001042424.3(NSD2):c.2154C>T (p.Phe718=)

https://sugi.bio/variant/nsd2-p-phe718

## Summary

**NSD2 p.Phe718= (c.2154C>T)** is classified **Likely benign** in NSD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-11). Ultra-rare (popmax 0.0165%, mid).

**At a glance:** Likely benign · review: Single submitter · rsID rs769815661 · 1 submitter · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the NSD2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NSD2](https://sugi.bio/atlas/gene/NSD2/) |
| Protein change (HGVS p.) | p.Phe718= |
| Coding change (HGVS c.) | c.2154C>T |
| MANE Select transcript | [NM_001042424](https://www.ncbi.nlm.nih.gov/nuccore/NM_001042424) |
| dbSNP | [rs769815661](https://www.ncbi.nlm.nih.gov/snp/rs769815661/) |
| Variant type | single nucleotide variant |
| Location | chr4:1953340-1953340 (GRCh38) |
| ClinVar | [VCV2178108](https://www.ncbi.nlm.nih.gov/clinvar/variation/2178108/) |

**All HGVS expressions:** `NC_000004.11:g.1955067C>T`, `NC_000004.12:g.1953340C>T`, `NG_009269.1:g.86945C>T`, `NM_001042424.3:c.2154C>T`, `NM_133330.3:c.2154C>T`, `NM_133331.3:c.2154C>T`, `NM_133335.4:c.2154C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -3.04, GERP -1.3 — fast-evolving / accelerated position
- CADD: **PHRED 12.74**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.26 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Pangolin: Δ**0.27** (loss), gain 0.00 / loss 0.27. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.000292% · FAF99 0.000211% · 1/6,062 in the highest group · 10/1,614,202 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,062 |
| South Asian | 0.0011% | 91,076 |
| European (non-Finnish) | 0.000678% | 147,504 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**NSD2** population constraint: LOEUF 0.139, pLI 1, missense-Z 5.6661; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **syndromic intellectual disability** — Definitive (AD)

## Protein context {#protein}

Residue **718** lies in a UniProt-annotated variant site (in raust).

AlphaFold model confidence (whole protein): pLDDT 66.22, 29% of residues very-high.

**24 experimental structure(s)** (PDB): [29HG](https://www.rcsb.org/structure/29HG), [29HH](https://www.rcsb.org/structure/29HH), [29HI](https://www.rcsb.org/structure/29HI), [5LSU](https://www.rcsb.org/structure/5LSU), [5VC8](https://www.rcsb.org/structure/5VC8), [6UE6](https://www.rcsb.org/structure/6UE6) — incl. mutant structure 7E8D.

## What this gene does {#gene-function}

*Describes the biological roles of NSD2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** NSD2's established molecular role includes histone H3K36 methyltransferase activity.


### Pathways affected {#pathways}

NSD2 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [G2/M DNA damage checkpoint](https://reactome.org/content/detail/R-HSA-69473) | curated |
| [Nonhomologous End-Joining (NHEJ)](https://reactome.org/content/detail/R-HSA-5693571) | curated |
| [PKMTs methylate histone lysines](https://reactome.org/content/detail/R-HSA-3214841) | curated |
| [Processing of DNA double-strand break ends](https://reactome.org/content/detail/R-HSA-5693607) | curated |
| [Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks](https://reactome.org/content/detail/R-HSA-5693565) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** histone H3K36 methyltransferase activity.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-07-11.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-07-11 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related NSD2 variant pages (same residue, condition, or type): [NSD2 p.Arg450Ter](/variant/nsd2-p-arg450ter), [NSD2 p.Arg755Ter](/variant/nsd2-p-arg755ter), [NSD2 p.Arg935Ter](/variant/nsd2-p-arg935ter), [NSD2 p.Pro895Leu](/variant/nsd2-p-pro895leu), [NSD2 p.Ala320Thr](/variant/nsd2-p-ala320thr), [NSD2 p.Ala383Gly](/variant/nsd2-p-ala383gly), [NSD2 p.Ala693Asp](/variant/nsd2-p-ala693asp), [NSD2 p.Ala965Thr](/variant/nsd2-p-ala965thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2178108). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*