# NM_012186.3(FOXE3):c.498C>A (p.Arg166=)

https://sugi.bio/variant/foxe3-p-arg166

## Summary

**FOXE3 p.Arg166= (c.498C>A)** is classified **Conflicting classifications of pathogenicity** in FOXE3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-29). Very rare (popmax 0.0018%, amr); Associated with Cardiovascular phenotype.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs747040897 · 2 submitters · 3 linked conditions · very rare (popmax 0.0018%, amr)

## For patients & families {#patients}

This is a change in the FOXE3 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to Cardiovascular phenotype.

*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 | [FOXE3](https://sugi.bio/atlas/gene/FOXE3/) |
| Protein change (HGVS p.) | p.Arg166= |
| Coding change (HGVS c.) | c.498C>A |
| MANE Select transcript | [NM_012186](https://www.ncbi.nlm.nih.gov/nuccore/NM_012186) |
| dbSNP | [rs747040897](https://www.ncbi.nlm.nih.gov/snp/rs747040897/) |
| Variant type | single nucleotide variant |
| Location | chr1:47416813-47416813 (GRCh38) |
| ClinVar | [VCV1744562](https://www.ncbi.nlm.nih.gov/clinvar/variation/1744562/) |

**All HGVS expressions:** `NC_000001.10:g.47882485C>A`, `NC_000001.11:g.47416813C>A`, `NG_016192.1:g.5742C>A`, `NM_012186.3:c.498C>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 2.263, GERP 0.812, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.02**. 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: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.0018%** (amr) · 1/55,690 in the highest group · 1/1,575,698 alleles overall — very rare (popmax 0.0018%, amr).

*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.*

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-04-29.

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

**Submission history:** 2 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-05-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-29 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [congenital primary aphakia](https://sugi.bio/atlas/disease/congenital-primary-aphakia/), [anterior segment dysgenesis](https://sugi.bio/atlas/disease/anterior-segment-dysgenesis/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, Anterior segment dysgenesis, Congenital primary aphakia, Ocular anterior segment dysgenesis, ANTERIOR SEGMENT DYSGENESIS 2, Anterior segment dysgenesis 2, multiple subtypes.

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 1744562). 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.*