# NM_001135649.3(FOXI3):c.701del (p.Phe234fs)

https://sugi.bio/variant/foxi3-p-phe234fs

## Summary

**FOXI3 p.Phe234fs (c.701del)** is classified **Likely pathogenic** in FOXI3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-16).

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter

## For patients & families {#patients}

This is a change in the FOXI3 gene that is considered likely disease-causing, 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 | [FOXI3](https://sugi.bio/atlas/gene/FOXI3/) |
| Protein change (HGVS p.) | p.Phe234fs |
| Coding change (HGVS c.) | c.701del |
| MANE Select transcript | [NM_001135649](https://www.ncbi.nlm.nih.gov/nuccore/NM_001135649) |
| Variant type | Deletion |
| Location | chr2:88448769-88448769 (GRCh38) |
| ClinVar | [VCV3774268](https://www.ncbi.nlm.nih.gov/clinvar/variation/3774268/) |

**All HGVS expressions:** `NC_000002.11:g.88748289del`, `NC_000002.12:g.88448770del`, `NM_001135649.3:c.701del`

## 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 2.132, GERP -1.88, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.73, pLI 0.65256. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (2 of 2)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- 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.

*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}

**FOXI3** population constraint: LOEUF 0.73, pLI 0.65256, missense-Z 0.38054; ClinGen dosage — haploinsufficiency 0/3, 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):

- **T-cell immunodeficiency** — Limited (AD)

## Protein context {#protein}

Residue **234** lies in a DNA-binding region; a UniProt-annotated variant site (in cfm2; decreased transcription factor activity; does not affect localization to the nucleus); a UniProt-annotated variant site (in cfm2; decreased transcription factor activity; localization to the nucleus but aggregating into granular foci); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 59.00, 18% of residues very-high.

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

*Describes the biological roles of FOXI3 (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:** FOXI3's established molecular role includes DNA-binding transcription factor activity, RNA polymerase II-specific. p.Phe234fs falls in a DNA-binding region.


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

**Molecular function:** DNA-binding transcription factor activity, RNA polymerase II-specific.

**Biological process:** pharyngeal system development.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-03-16.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-03-16 |

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

## Same-residue context {#hotspot}

Residue **234** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [FOXI3 p.Phe234Val](/variant/foxi3-p-phe234val). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related FOXI3 variant pages (same residue, condition, or type): [FOXI3 p.Phe234Leu](/variant/foxi3-p-phe234leu), [FOXI3 p.Phe234Val](/variant/foxi3-p-phe234val), [FOXI3 p.Tyr75fs](/variant/foxi3-p-tyr75fs), [FOXI3 p.Gly103fs](/variant/foxi3-p-gly103fs), [FOXI3 p.Ala113fs](/variant/foxi3-p-ala113fs), [FOXI3 p.Ala116_Ala124del](/variant/foxi3-p-ala116-ala124del), [FOXI3 p.Ala122_Ala124del](/variant/foxi3-p-ala122-ala124del), [FOXI3 p.Ala70_Ala74del](/variant/foxi3-p-ala70-ala74del).

### 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 3774268). 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.*