# NM_001447.3(FAT2):c.10474A>C (p.Arg3492=)

https://sugi.bio/variant/fat2-p-arg3492

## Summary

**FAT2 p.Arg3492= (c.10474A>C)** is classified **Likely benign** in FAT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-22). Very rare (popmax 0.000424%, nfe).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · very rare (popmax 0.000424%, nfe)

## For patients & families {#patients}

This is a change in the FAT2 gene that is classified as likely benign — not considered disease-causing, 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 | [FAT2](https://sugi.bio/atlas/gene/FAT2/) |
| Protein change (HGVS p.) | p.Arg3492= |
| Coding change (HGVS c.) | c.10474A>C |
| MANE Select transcript | [NM_001447](https://www.ncbi.nlm.nih.gov/nuccore/NM_001447) |
| Variant type | single nucleotide variant |
| Location | chr5:151525800-151525800 (GRCh38) |
| ClinVar | [VCV4763929](https://www.ncbi.nlm.nih.gov/clinvar/variation/4763929/) |

**All HGVS expressions:** `NC_000005.10:g.151525800T>G`, `NC_000005.9:g.150905361T>G`, `NG_046979.1:g.131341A>C`, `NM_001447.3:c.10474A>C`

## 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 1.144, GERP -0.318, phastCons 0.177 — weakly conserved position
- CADD: **PHRED 4.995**. 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 (T>A, Δ0.72 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 **0.000424%** (nfe) · FAF95 0.000124% · FAF99 9e-05% · 5/1,180,040 in the highest group · 5/1,614,140 alleles overall — very rare (popmax 0.000424%, 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}

**FAT2** population constraint: LOEUF 0.554, pLI 3.475e-13, missense-Z 4.0706. *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 **3492** lies in the cadherin 31 domain.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-22.

**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 | 2025-11-22 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related FAT2 variant pages (same residue, condition, or type): [FAT2 p.Ala1009Val](/variant/fat2-p-ala1009val), [FAT2 p.Ala1078Thr](/variant/fat2-p-ala1078thr), [FAT2 p.Ala1079Asp](/variant/fat2-p-ala1079asp), [FAT2 p.Ala1975Glu](/variant/fat2-p-ala1975glu), [FAT2 p.Ala2491Glu](/variant/fat2-p-ala2491glu), [FAT2 p.Ala249Val](/variant/fat2-p-ala249val), [FAT2 p.Ala2587Val](/variant/fat2-p-ala2587val), [FAT2 p.Ala2618Thr](/variant/fat2-p-ala2618thr).

### 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 4763929). 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.*