# NM_012108.4(STAP1):c.421G>T (p.Val141Phe)

https://sugi.bio/variant/stap1-p-val141phe

## Summary

**STAP1 p.Val141Phe (c.421G>T)** is classified **Uncertain significance** in STAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-30). AlphaMissense: ambiguous (0.5084); Very rare (popmax 0.00133%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the STAP1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [STAP1](https://sugi.bio/atlas/gene/STAP1/) |
| Protein change (HGVS p.) | p.Val141Phe |
| Coding change (HGVS c.) | c.421G>T |
| MANE Select transcript | [NM_012108](https://www.ncbi.nlm.nih.gov/nuccore/NM_012108) |
| Variant type | single nucleotide variant |
| Location | chr4:67581362-67581362 (GRCh38) |
| ClinVar | [VCV4176151](https://www.ncbi.nlm.nih.gov/clinvar/variation/4176151/) |

**All HGVS expressions:** `NC_000004.11:g.68447080G>T`, `NC_000004.12:g.67581362G>T`, `NG_047142.1:g.27635G>T`, `NM_001317769.2:c.421G>T`, `NM_012108.4:c.421G>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.5084) — no call either way
- REVEL 0.164 (moderately benign-leaning)
- SaProt LLR -12.921 (damaging)
- → **In-silico consensus:** SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate
- SpliceAI predicts **acceptor gain** (Δ 0.35) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 8.392, GERP 1.83, phastCons 1 — highly conserved
- CADD: **PHRED 26.5**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.35**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.35**, donor gain **0.00**.
- Pangolin: Δ**0.27** (gain), gain 0.27 / loss 0.00. Agrees with SpliceAI. 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 **0.00133%** (afr) · 1/74,922 in the highest group · 1/1,613,980 alleles overall — very rare (popmax 0.00133%, afr).

*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.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.06, 71% of residues very-high.

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

*Describes the biological roles of STAP1 (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:** STAP1's established molecular role includes chromatin binding.


### Pathways affected {#pathways}

STAP1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Transcriptional Regulation by E2F6](https://reactome.org/content/detail/R-HSA-8953750) | curated |

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

**Molecular function:** chromatin binding, transcription corepressor activity, beta-tubulin binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, microtubule cytoskeleton organization, centrosome cycle, positive regulation of non-canonical NF-kappaB signal transduction.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-30.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-30 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related STAP1 variant pages (same residue, condition, or type): [STAP1 p.Val141=](/variant/stap1-p-val141), [STAP1 p.Gln192Arg](/variant/stap1-p-gln192arg), [STAP1 p.Leu288Val](/variant/stap1-p-leu288val), [STAP1 c.120+6T>C](/variant/stap1-c-120-plus-6t-c), [STAP1 c.192+102T>C](/variant/stap1-c-192-plus-102t-c), [STAP1 c.192+10T>C](/variant/stap1-c-192-plus-10t-c), [STAP1 c.530+11A>G](/variant/stap1-c-530-plus-11a-g), [STAP1 c.530+60A>G](/variant/stap1-c-530-plus-60a-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 4176151). 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.*