# NM_001048166.1(STIL):c.66del (p.Pro23fs)

https://sugi.bio/variant/stil-p-pro23fs

## Summary

**STIL p.Pro23fs (c.66del)** is classified **Uncertain significance** in STIL (ClinVar, Single submitter, 1 submitter; last evaluated 2019-01-01). No gnomAD frequency available for this variant; Associated with microcephaly 7, primary, autosomal recessive.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1645910850 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the STIL gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to microcephaly 7, primary, autosomal recessive.

*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/0015580/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [STIL](https://sugi.bio/atlas/gene/STIL/) |
| Protein change (HGVS p.) | p.Pro23fs |
| Coding change (HGVS c.) | c.66del |
| MANE Select transcript | [NM_001048166](https://www.ncbi.nlm.nih.gov/nuccore/NM_001048166) |
| dbSNP | [rs1645910850](https://www.ncbi.nlm.nih.gov/snp/rs1645910850/) |
| Variant type | Deletion |
| Location | chr1:47304975-47304975 (GRCh38) |
| ClinVar | [VCV982579](https://www.ncbi.nlm.nih.gov/clinvar/variation/982579/) |

**All HGVS expressions:** `NC_000001.10:g.47770647del`, `NC_000001.11:g.47304975del`, `NG_012126.1:g.14173del`, `NM_001048166.1:c.66del`, `NM_001282936.1:c.66del`, `NM_001282937.1:c.66del`, `NM_001282938.1:c.66del`, `NM_001282939.1:c.66del`, `NM_001377417.1:c.66del`, `NM_003035.2:c.66del`

## 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 11.587, GERP 2.3, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.575, pLI 0.0050023. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 17**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion 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}

**STIL** population constraint: LOEUF 0.575, pLI 0.0050023, missense-Z 2.1726; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/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):

- **autosomal recessive primary microcephaly** — Definitive (AR)

## Protein context {#protein}

Residue **23** lies in the 'interaction with rbm14' region.

AlphaFold model confidence (whole protein): pLDDT 54.29, 20% of residues very-high.

**5 experimental structure(s)** (PDB): [4YYP](https://www.rcsb.org/structure/4YYP), [5LHW](https://www.rcsb.org/structure/5LHW), [5LHZ](https://www.rcsb.org/structure/5LHZ), [8OYK](https://www.rcsb.org/structure/8OYK), [8OYL](https://www.rcsb.org/structure/8OYL) — incl. mutant structure 8OYK.

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

*Describes the biological roles of STIL (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:** STIL's established molecular role includes identical protein binding. p.Pro23fs falls in the interaction with rbm14 region.


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

**Molecular function:** identical protein binding.

**Biological process:** mitotic spindle organization, regulation of centriole replication, positive regulation of centriole replication, centrosome duplication, protein localization to centrosome, positive regulation of G1/S transition of mitotic cell cycle.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-01-01.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, University of Leipzig Medical Center | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-01-01 |

## Associated conditions {#conditions}

[microcephaly 7, primary, autosomal recessive](https://sugi.bio/atlas/disease/microcephaly-7-primary-autosomal-recessive/).

**Reported phenotype names (ClinVar):** Microcephaly 7, primary, autosomal recessive.

## Similar variants {#similar}

Related STIL variant pages (same residue, condition, or type): [STIL p.Asp830fs](/variant/stil-p-asp830fs), [STIL p.Pro23Leu](/variant/stil-p-pro23leu), [STIL p.Leu1219_Val1220insTer](/variant/stil-p-leu1219-val1220inster), [STIL p.Leu782fs](/variant/stil-p-leu782fs), [STIL c.*203C>T](/variant/stil-c-star-203c-t), [STIL c.*599A>G](/variant/stil-c-star-599a-g), [STIL p.Ala543Val](/variant/stil-p-ala543val), [STIL p.Arg742His](/variant/stil-p-arg742his).

### 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 982579). 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.*