# NM_022489.4(INF2):c.3709del (p.Ser1237fs)

https://sugi.bio/variant/inf2-p-ser1237fs

## Summary

**INF2 p.Ser1237fs (c.3709del)** is classified **Uncertain significance** in INF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-28). No gnomAD frequency available for this variant; Associated with Charcot-Marie-Tooth disease dominant intermediate E.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2541955759 · 1 submitter · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the INF2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Charcot-Marie-Tooth disease dominant intermediate E.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Not applicable |
| Age of onset (of this condition) | No data available |
| Diagnostic panels | INF2 is a diagnostic-grade gene on 5 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012011/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [INF2](https://sugi.bio/atlas/gene/INF2/) |
| Protein change (HGVS p.) | p.Ser1237fs |
| Coding change (HGVS c.) | c.3709del |
| MANE Select transcript | [NM_022489](https://www.ncbi.nlm.nih.gov/nuccore/NM_022489) |
| dbSNP | [rs2541955759](https://www.ncbi.nlm.nih.gov/snp/rs2541955759/) |
| Variant type | Deletion |
| Location | chr14:104715297-104715297 (GRCh38) |
| ClinVar | [VCV2951348](https://www.ncbi.nlm.nih.gov/clinvar/variation/2951348/) |

**All HGVS expressions:** `NC_000014.8:g.105181635del`, `NC_000014.9:g.104715298del`, `NG_027684.1:g.30693del`, `NG_027684.2:g.30682del`, `NG_130346.1:g.723del`, `NM_001031714.4:c.3694+442del`, `NM_001426863.1:c.3709delT`, `NM_001426864.1:c.3709delT`, `NM_022489.4:c.3709del`, `NR_190061.1:n.3840delT`

## 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 2.755, GERP 5.22, phastCons 0.942 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.526, pLI 0.33382. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **within the last 50 nt of the penultimate exon (22 of 23, 43 nt from its 3' end)** — 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.
- 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}

**INF2** population constraint: LOEUF 0.526, pLI 0.33382, missense-Z 1.7391; 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):

- **Charcot-Marie-Tooth disease dominant intermediate E** — Definitive (AD)

## Protein context {#protein}

Residue **1237** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 67.34, 30% of residues very-high.

**10 experimental structure(s)** (PDB): [8RV2](https://www.rcsb.org/structure/8RV2), [9AZ4](https://www.rcsb.org/structure/9AZ4), [9AZP](https://www.rcsb.org/structure/9AZP), [9AZQ](https://www.rcsb.org/structure/9AZQ), [9B03](https://www.rcsb.org/structure/9B03), [9B0K](https://www.rcsb.org/structure/9B0K).

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-08-28.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-08-28 |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease dominant intermediate E](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-dominant-intermediate-e/), [focal segmental glomerulosclerosis 5](https://sugi.bio/atlas/disease/focal-segmental-glomerulosclerosis-5/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease dominant intermediate E, Focal segmental glomerulosclerosis 5, CHARCOT-MARIE-TOOTH NEUROPATHY WITH FOCAL SEGMENTAL GLOMERULONEPHRITIS.

## Similar variants {#similar}

Related INF2 variant pages (same residue, condition, or type): [INF2 p.Ser1237Thr](/variant/inf2-p-ser1237thr), [INF2 p.Ala164_Asp166del](/variant/inf2-p-ala164-asp166del), [INF2 p.Leu406_Ser409del](/variant/inf2-p-leu406-ser409del), [INF2 p.Lys1243fs](/variant/inf2-p-lys1243fs), [INF2 p.Pro459_Pro462del](/variant/inf2-p-pro459-pro462del), [INF2 p.Ser1215fs](/variant/inf2-p-ser1215fs), [INF2 p.Thr1242fs](/variant/inf2-p-thr1242fs), [INF2 c.2310+12del](/variant/inf2-c-2310-plus-12del).

### 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 2951348). 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.*