# NM_022489.4(INF2):c.858G>A (p.Pro286=)

https://sugi.bio/variant/inf2-p-pro286

## Summary

**INF2 p.Pro286= (c.858G>A)** is classified **Likely benign** in INF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-16). Very rare (popmax 0.00802%, afr); Associated with focal segmental glomerulosclerosis 5.

**At a glance:** Likely benign · review: Single submitter · rsID rs762527373 · 1 submitter · 2 linked conditions · very rare (popmax 0.00802%, afr)

## For patients & families {#patients}

This is a change in the INF2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to focal segmental glomerulosclerosis 5.

*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/0015636/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.Pro286= |
| Coding change (HGVS c.) | c.858G>A |
| MANE Select transcript | [NM_022489](https://www.ncbi.nlm.nih.gov/nuccore/NM_022489) |
| dbSNP | [rs762527373](https://www.ncbi.nlm.nih.gov/snp/rs762527373/) |
| Variant type | single nucleotide variant |
| Location | chr14:104706924-104706924 (GRCh38) |
| ClinVar | [VCV1122341](https://www.ncbi.nlm.nih.gov/clinvar/variation/1122341/) |

**All HGVS expressions:** `NC_000014.8:g.105173261G>A`, `NC_000014.9:g.104706924G>A`, `NG_027684.1:g.22319G>A`, `NM_001031714.4:c.858G>A`, `NM_022489.4:c.858G>A`

## 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 -14.875, GERP -13.3 — fast-evolving / accelerated position
- CADD: **PHRED 0.196**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.60 acceptor 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 **0.00802%** (afr) · FAF95 0.00347% · FAF99 0.00229% · 6/74,846 in the highest group · 25/1,604,090 alleles overall — very rare (popmax 0.00802%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00802% | 12,474 |
| East Asian | 0.00446% | 22,434 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00339% | 29,510 |
| South Asian | 0.0022% | 45,498 |
| Finnish (not grpmax-eligible) | 0.0018% | 55,472 |
| Admixed American | 0.00167% | 59,902 |
| European (non-Finnish) | 0.00102% | 98,275 |

*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 **286** lies in the gbd/fh3 domain.

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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-16.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-02-16 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related INF2 variant pages (same residue, condition, or type): [INF2 p.Arg177Cys](/variant/inf2-p-arg177cys), [INF2 p.Arg214Cys](/variant/inf2-p-arg214cys), [INF2 p.Arg214His](/variant/inf2-p-arg214his), [INF2 p.Arg218Gln](/variant/inf2-p-arg218gln), [INF2 p.Arg218Trp](/variant/inf2-p-arg218trp), [INF2 p.Arg91Gly](/variant/inf2-p-arg91gly), [INF2 p.Asn202Asp](/variant/inf2-p-asn202asp), [INF2 p.Glu184Lys](/variant/inf2-p-glu184lys).

### 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 1122341). 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.*