# NM_006832.3(FERMT2):c.1250C>G (p.Pro417Arg)

https://sugi.bio/variant/fermt2-p-pro417arg

## Summary

**FERMT2 p.Pro417Arg (c.1250C>G)** is classified **Uncertain significance** in FERMT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely pathogenic (0.8523); Ultra-rare (popmax 0.036%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · ultra-rare (popmax 0.036%, afr)

## For patients & families {#patients}

This is a change in the FERMT2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [FERMT2](https://sugi.bio/atlas/gene/FERMT2/) |
| Protein change (HGVS p.) | p.Pro417Arg |
| Coding change (HGVS c.) | c.1250C>G |
| MANE Select transcript | [NM_006832](https://www.ncbi.nlm.nih.gov/nuccore/NM_006832) |
| Variant type | single nucleotide variant |
| Location | chr14:52872822-52872822 (GRCh38) |
| ClinVar | [VCV4024480](https://www.ncbi.nlm.nih.gov/clinvar/variation/4024480/) |

**All HGVS expressions:** `NC_000014.8:g.53339540G>C`, `NC_000014.9:g.52872822G>C`, `NM_001134999.2:c.1250C>G`, `NM_001135000.2:c.1250C>G`, `NM_006832.3:c.1250C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8523)
- REVEL 0.777 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -17.46 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.705, GERP 1.88, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.6**. 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 0.80** across the covering region of the MANE Select transcript (52,858,380–52,950,568), spanning 92,188 bp. Chi-square p 7.5e-09. 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 (G>A, Δ0.20 donor loss), 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 **0.036%** (afr) · FAF95 0.0254% · FAF99 0.0218% · 27/75,028 in the highest group · 36/1,613,862 alleles overall — ultra-rare (popmax 0.036%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.036% | 2,779 |
| Admixed American | 0.0133% | 7,500 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,490 |

*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}

**FERMT2** population constraint: LOEUF 0.304, pLI 1, missense-Z 2.3044. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **417** lies in the ferm domain; the ph domain.

AlphaFold model confidence (whole protein): pLDDT 80.79, 50% of residues very-high.

**6 experimental structure(s)** (PDB): [2LGX](https://www.rcsb.org/structure/2LGX), [2LKO](https://www.rcsb.org/structure/2LKO), [2MSU](https://www.rcsb.org/structure/2MSU), [4F7H](https://www.rcsb.org/structure/4F7H), [6U4N](https://www.rcsb.org/structure/6U4N), [6XTJ](https://www.rcsb.org/structure/6XTJ).

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

*Describes the biological roles of FERMT2 (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:** FERMT2's established molecular role includes actin binding. p.Pro417Arg falls in the ferm domain.


### Pathways affected {#pathways}

FERMT2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cell-extracellular matrix interactions](https://reactome.org/content/detail/R-HSA-446353) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | curated |

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

**Molecular function:** actin binding, phosphatidylinositol-3,4,5-trisphosphate binding, protein kinase binding, type I transforming growth factor beta receptor binding, protein serine/threonine kinase activator activity, SMAD binding.

**Biological process:** cell adhesion, cell-matrix adhesion, transforming growth factor beta receptor signaling pathway, integrin-mediated signaling pathway, positive regulation of epithelial to mesenchymal transition, Wnt signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-10 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related FERMT2 variant pages (same residue, condition, or type): [FERMT2 p.Pro417Gln](/variant/fermt2-p-pro417gln), [FERMT2 c.1603-562A>G](/variant/fermt2-c-1603-minus-562a-g), [FERMT2 c.1603-565G>C](/variant/fermt2-c-1603-minus-565g-c), [FERMT2 c.1603-566G>C](/variant/fermt2-c-1603-minus-566g-c), [FERMT2 p.Ala122Gly](/variant/fermt2-p-ala122gly), [FERMT2 p.Ala298Gly](/variant/fermt2-p-ala298gly), [FERMT2 p.Ala481Val](/variant/fermt2-p-ala481val), [FERMT2 p.Ala537Val](/variant/fermt2-p-ala537val).

### 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 4024480). 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.*