# NM_022489.4(INF2):c.271C>T (p.Arg91Cys)

https://sugi.bio/variant/inf2-p-arg91cys

## Summary

**INF2 p.Arg91Cys (c.271C>T)** is classified **Uncertain significance** in INF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-12). AlphaMissense: likely benign (0.281); Very rare (popmax 8.5e-05%, nfe); Associated with Charcot-Marie-Tooth disease dominant intermediate E.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs200247054 · 1 submitter · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 8.5e-05%, nfe)

## 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.Arg91Cys |
| Coding change (HGVS c.) | c.271C>T |
| MANE Select transcript | [NM_022489](https://www.ncbi.nlm.nih.gov/nuccore/NM_022489) |
| dbSNP | [rs200247054](https://www.ncbi.nlm.nih.gov/snp/rs200247054/) |
| Variant type | single nucleotide variant |
| Location | chr14:104701636-104701636 (GRCh38) |
| ClinVar | [VCV1063428](https://www.ncbi.nlm.nih.gov/clinvar/variation/1063428/) |

**All HGVS expressions:** `NC_000014.8:g.105167973C>T`, `NC_000014.9:g.104701636C>T`, `NG_027684.1:g.17031C>T`, `NM_001031714.4:c.271C>T`, `NM_022489.4:c.271C>T`, `NM_032714.3:c.271C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.281)
- REVEL 0.616 (indeterminate)
- SaProt LLR -9.107 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 5.794, GERP 7.26, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 27.5**. 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.*
- Regional missense constraint: **o/e 0.72** across the covering region of the MANE Select transcript (104,701,524–104,706,968), spanning 5,444 bp. Chi-square p 1.4e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.39 donor 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 **8.5e-05%** (nfe) · 1/1,176,360 in the highest group · 1/1,600,772 alleles overall — very rare (popmax 8.5e-05%, nfe).

*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 **91** 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-07-12.

**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 | 2022-07-12 |

## 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.

## Same-residue context {#hotspot}

Residue **91** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [INF2 p.Arg91Gly](/variant/inf2-p-arg91gly). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related INF2 variant pages (same residue, condition, or type): [INF2 p.Arg91Gly](/variant/inf2-p-arg91gly), [INF2 p.Arg91Leu](/variant/inf2-p-arg91leu), [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.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 1063428). 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.*