# NM_022489.4(INF2):c.879G>A (p.Ser293=)

https://sugi.bio/variant/inf2-p-ser293

## Summary

**INF2 p.Ser293= (c.879G>A)** is classified **Conflicting classifications of pathogenicity** in INF2 (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-02-02). Low-frequency (popmax 2.14%, amr); Associated with focal segmental glomerulosclerosis 5.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs184709736 · 14 submitters · 3 linked conditions · low-frequency (popmax 2.14%, amr)

## For patients & families {#patients}

This is a change in the INF2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 14 submitters, 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.Ser293= |
| Coding change (HGVS c.) | c.879G>A |
| MANE Select transcript | [NM_022489](https://www.ncbi.nlm.nih.gov/nuccore/NM_022489) |
| dbSNP | [rs184709736](https://www.ncbi.nlm.nih.gov/snp/rs184709736/) |
| Variant type | single nucleotide variant |
| Location | chr14:104706945-104706945 (GRCh38) |
| ClinVar | [VCV261629](https://www.ncbi.nlm.nih.gov/clinvar/variation/261629/) |

**All HGVS expressions:** `NC_000014.8:g.105173282G>A`, `NC_000014.9:g.104706945G>A`, `NG_027684.1:g.22340G>A`, `NM_001031714.4:c.879G>A`, `NM_022489.4:c.879G>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 -20, GERP -14.5 — fast-evolving / accelerated position
- CADD: **PHRED 0.046**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. This allele is not in the release, so all four of its deltas are under 0.2. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, and here that is proven rather than inferred: a different substitution at this very position, G>T, IS in the release and scores Δ0.60 acceptor gain, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **2.14%** (amr) · FAF95 2.04% · FAF99 2.01% · 1,283/59,898 in the highest group · 11,053/1,603,198 alleles overall — low-frequency (popmax 2.14%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 2.14% | 47 |
| European (non-Finnish) | 0.726% | 138 |
| Remaining individuals (not grpmax-eligible) | 0.698% | 143 |
| Middle Eastern | 0.671% | 149 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.414% | 242 |
| South Asian | 0.396% | 253 |
| African / African-American | 0.197% | 506 |
| Finnish (not grpmax-eligible) | 0.196% | 510 |
| East Asian | 0.00446% | 22,424 |

*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 **293** 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-02.

**Submitter consensus:** conflicting (12 Benign, 1 Likely benign, 1 Uncertain significance).

**Submission history:** 14 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| Fulgent Genetics, Fulgent Genetics | Benign | criteria provided, single submitter | clinical testing | 2021-07-20 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-07-11 |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2018-12-11 |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-12-12 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-07-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-02 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-27 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2016-07-07 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2023-02-21 |

## Associated conditions {#conditions}

[focal segmental glomerulosclerosis 5](https://sugi.bio/atlas/disease/focal-segmental-glomerulosclerosis-5/), [kidney disorder](https://sugi.bio/atlas/disease/kidney-disorder/), [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, not specified, not provided, Charcot-Marie-Tooth disease dominant intermediate E, Inborn genetic diseases, Kidney disorder, CHARCOT-MARIE-TOOTH NEUROPATHY WITH FOCAL SEGMENTAL GLOMERULONEPHRITIS, Kidney disease, Kidney Diseases, renal disorder.

## Similar variants {#similar}

Related INF2 variant pages (same residue, condition, or type): [INF2 p.Ser293Leu](/variant/inf2-p-ser293leu), [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).

### 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 261629). 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.*