# NM_138927.4(SON):c.1414_1423delinsTTGCGTCTGTGG (p.Pro472fs)

https://sugi.bio/variant/son-p-pro472fs

## Summary

**SON p.Pro472fs (c.1414_1423delinsTTGCGTCTGTGG)** is classified **Pathogenic** in SON (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-04). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1555898264 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the SON gene that is reported as disease-causing, but on limited review, 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 | [SON](https://sugi.bio/atlas/gene/SON/) |
| Protein change (HGVS p.) | p.Pro472fs |
| Coding change (HGVS c.) | c.1414_1423delinsTTGCGTCTGTGG |
| MANE Select transcript | [NM_138927](https://www.ncbi.nlm.nih.gov/nuccore/NM_138927) |
| dbSNP | [rs1555898264](https://www.ncbi.nlm.nih.gov/snp/rs1555898264/) |
| Variant type | Indel |
| Location | chr21:33550645-33550654 (GRCh38) |
| ClinVar | [VCV524167](https://www.ncbi.nlm.nih.gov/clinvar/variation/524167/) |

**All HGVS expressions:** `NC_000021.8:g.34922951_34922960delinsTTGCGTCTGTGG`, `NC_000021.9:g.33550645_33550654delinsTTGCGTCTGTGG`, `NG_052981.1:g.12608_12617delinsTTGCGTCTGTGG`, `NM_001291411.2:c.1414_1423delinsTTGCGTCTGTGG`, `NM_001291412.3:c.244+4266_244+4275delinsTTGCGTCTGTGG`, `NM_032195.2:c.1414_1423delCCACCTGTGAinsTTGCGTCTGTGG`, `NM_032195.3:c.1414_1423delinsTTGCGTCTGTGG`, `NM_138927.4:c.1414_1423delinsTTGCGTCTGTGG`, `NR_103797.2:n.1469_1478delinsTTGCGTCTGTGG`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 5.977, GERP 4.55, phastCons 1 — highly conserved position (PP3-type support)
- 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 indel 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}


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.


### 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** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-05-04.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2018-05-04 |

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

## Similar variants {#similar}

Related SON variant pages (same residue, condition, or type): [SON p.Pro472Ser](/variant/son-p-pro472ser), [SON p.Pro472=](/variant/son-p-pro472), [SON p.Ala1768_Val1772del](/variant/son-p-ala1768-val1772del), [SON p.Leu1507_Glu1512delinsAlaCysSerIle](/variant/son-p-leu1507-glu1512delinsalacysserile), [SON c.245-485_273delinsGTTG](/variant/son-c-245-minus-485-273delinsgttg), [SON p.Glu315fs](/variant/son-p-glu315fs), [SON p.Gly1486_Ile1487delinsAspTer](/variant/son-p-gly1486-ile1487delinsaspter), [SON p.Leu993fs](/variant/son-p-leu993fs).

### 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 524167). 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.*