# NM_138927.4(SON):c.6002_6003insCC (p.Arg2002fs)

https://sugi.bio/variant/son-p-arg2002fs

## Summary

**SON p.Arg2002fs (c.6002_6003insCC)** is classified **Pathogenic/Likely pathogenic** in SON (ClinVar, No assertion criteria, 2 submitters; last evaluated 2016-11-02). No gnomAD frequency available for this variant; Associated with ZTTK syndrome.

**At a glance:** Pathogenic/Likely pathogenic · review: No assertion criteria · rsID rs886039775 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the SON gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to ZTTK syndrome.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013489/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SON](https://sugi.bio/atlas/gene/SON/) |
| Protein change (HGVS p.) | p.Arg2002fs |
| Coding change (HGVS c.) | c.6002_6003insCC |
| MANE Select transcript | [NM_138927](https://www.ncbi.nlm.nih.gov/nuccore/NM_138927) |
| dbSNP | [rs886039775](https://www.ncbi.nlm.nih.gov/snp/rs886039775/) |
| Variant type | Insertion |
| Location | chr21:33555232-33555233 (GRCh38) |
| ClinVar | [VCV265775](https://www.ncbi.nlm.nih.gov/clinvar/variation/265775/) |

**All HGVS expressions:** `NC_000021.8:g.34927539_34927540insCC`, `NC_000021.9:g.33555233_33555234insCC`, `NG_052981.1:g.17196_17197insCC`, `NM_001291411.2:c.6002_6003insCC`, `NM_001291412.3:c.245-1923_245-1922insCC`, `NM_032195.3:c.6002_6003insCC`, `NM_138927.4:c.6002_6003insCC`, `NR_103797.2:n.6057_6058insCC`

## 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 0.602, GERP 4.34, phastCons 0.746 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.051, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 12**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no insertion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**SON** population constraint: LOEUF 0.051, pLI 1, missense-Z 2.5949; 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):

- **ZTTK syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **2002** lies in the 'disordered' region; the '2 x 19 aa repeats of p-s-r-r-r-r-s-r-s-v-v-r-r-r-s-f-s-i-s' region.

AlphaFold model confidence (whole protein): pLDDT 36.48, 2% of residues very-high.

**4 experimental structure(s)** (PDB): [7CIQ](https://www.rcsb.org/structure/7CIQ), [7CIR](https://www.rcsb.org/structure/7CIR), [7CIS](https://www.rcsb.org/structure/7CIS), [7DYN](https://www.rcsb.org/structure/7DYN).

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

*Describes the biological roles of SON (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:** SON's established molecular role includes RNA binding. p.Arg2002fs falls in the disordered region.


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

**Molecular function:** RNA binding.

**Biological process:** microtubule cytoskeleton organization, mitotic cytokinesis, mRNA processing, negative regulation of apoptotic process, regulation of RNA splicing, regulation of mRNA splicing, via spliceosome.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2016-11-02.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (2016); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2016-11-02 |
| University of Washington Center for Mendelian Genomics, University of Washington | Likely pathogenic | no assertion criteria provided | research | 2016-09-01 |

## Associated conditions {#conditions}

[ZTTK syndrome](https://sugi.bio/atlas/disease/zttk-syndrome/).

**Reported phenotype names (ClinVar):** ZTTK syndrome, ZTTK MULTIPLE CONGENITAL ANOMALIES-MENTAL RETARDATION SYNDROME, Zhu-Tokita-Takenouchi-Kim Syndrome.

## Similar variants {#similar}

Related SON variant pages (same residue, condition, or type): [SON p.Val1338fs](/variant/son-p-val1338fs), [SON c.6321+1G>A](/variant/son-c-6321-plus-1g-a), [SON p.Arg1081Ter](/variant/son-p-arg1081ter), [SON p.Arg1112Ter](/variant/son-p-arg1112ter), [SON p.Arg1906fs](/variant/son-p-arg1906fs), [SON p.Arg1908fs](/variant/son-p-arg1908fs), [SON p.Arg2008Ter](/variant/son-p-arg2008ter), [SON p.Gln874fs](/variant/son-p-gln874fs).

### 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 265775). 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.*