# NM_052844.4(DYNC2I2):c.140C>T (p.Ser47Phe)

https://sugi.bio/variant/dync2i2-p-ser47phe

## Summary

**DYNC2I2 p.Ser47Phe (c.140C>T)** is classified **Uncertain significance** in DYNC2I2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-07). AlphaMissense: likely benign (0.18); Very rare (popmax 0.00633%, sas); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1860830386 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00633%, sas)

## For patients & families {#patients}

This is a change in the DYNC2I2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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 | [DYNC2I2](https://sugi.bio/atlas/gene/DYNC2I2/) |
| Protein change (HGVS p.) | p.Ser47Phe |
| Coding change (HGVS c.) | c.140C>T |
| MANE Select transcript | [NM_052844](https://www.ncbi.nlm.nih.gov/nuccore/NM_052844) |
| dbSNP | [rs1860830386](https://www.ncbi.nlm.nih.gov/snp/rs1860830386/) |
| Variant type | single nucleotide variant |
| Location | chr9:128656587-128656587 (GRCh38) |
| ClinVar | [VCV2109721](https://www.ncbi.nlm.nih.gov/clinvar/variation/2109721/) |

**All HGVS expressions:** `NC_000009.11:g.131418866G>A`, `NC_000009.12:g.128656587G>A`, `NG_034056.1:g.5264C>T`, `NG_117658.1:g.429G>A`, `NM_052844.3:c.140C>T`, `NM_052844.4:c.140C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.18)
- REVEL 0.596 (indeterminate)
- SaProt LLR -8.276 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 8.838, GERP 2.22, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.4**. 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.*
- Regional missense constraint: **o/e 1.02** across the covering region of the MANE Select transcript (128,633,747–128,656,726), spanning 22,979 bp. Chi-square p 0.59. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.46 donor gain), 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.*
- Population frequency (gnomAD v4.1): grpmax **0.00633%** (sas) · FAF95 0.00245% · FAF99 0.00154% · 5/78,940 in the highest group · 6/1,485,568 alleles overall — very rare (popmax 0.00633%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00633% | 15,788 |
| Remaining individuals (not grpmax-eligible) | 0.00174% | 57,508 |

*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}

**DYNC2I2** population constraint: LOEUF 1.036, pLI 8.6153e-12, missense-Z -0.55611. *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):

- **short-rib thoracic dysplasia 11 with or without polydactyly** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 82.66, 65% of residues very-high.

**4 experimental structure(s)** (PDB): [6RLB](https://www.rcsb.org/structure/6RLB), [6SC2](https://www.rcsb.org/structure/6SC2), [8RGG](https://www.rcsb.org/structure/8RGG), [8RGH](https://www.rcsb.org/structure/8RGH).

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

*Describes the biological roles of DYNC2I2 (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:** DYNC2I2's established molecular role includes dynein light chain binding.


### Pathways affected {#pathways}

DYNC2I2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Intraflagellar transport](https://reactome.org/content/detail/R-HSA-5620924) | curated |

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

**Molecular function:** dynein light chain binding.

**Biological process:** intraciliary retrograde transport, cilium assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-06-07.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-03-12 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [short-rib thoracic dysplasia 11 with or without polydactyly](https://sugi.bio/atlas/disease/short-rib-thoracic-dysplasia-11-with-or-without-polydactyly/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Short-rib thoracic dysplasia 11 with or without polydactyly, SHORT-RIB THORACIC DYSPLASIA 11 WITHOUT POLYDACTYLY.

## Similar variants {#similar}

Related DYNC2I2 variant pages (same residue, condition, or type): [DYNC2I2 p.Ser47Cys](/variant/dync2i2-p-ser47cys), [DYNC2I2 c.1372+1G>A](/variant/dync2i2-c-1372-plus-1g-a), [DYNC2I2 p.Arg121Ter](/variant/dync2i2-p-arg121ter), [DYNC2I2 p.Arg182Trp](/variant/dync2i2-p-arg182trp), [DYNC2I2 p.Arg447Trp](/variant/dync2i2-p-arg447trp), [DYNC2I2 p.Ala131Val](/variant/dync2i2-p-ala131val), [DYNC2I2 p.Ala13Gly](/variant/dync2i2-p-ala13gly), [DYNC2I2 p.Ala219Thr](/variant/dync2i2-p-ala219thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2109721). 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.*