# NM_015267.4(CUX2):c.1677C>T (p.Ala559=)

https://sugi.bio/variant/cux2-p-ala559

## Summary

**CUX2 p.Ala559= (c.1677C>T)** is classified **Likely benign** in CUX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-01). Ultra-rare (popmax 0.033%, mid).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs199689266 · 2 submitters · ultra-rare (popmax 0.033%, mid)

## For patients & families {#patients}

This is a change in the CUX2 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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 | [CUX2](https://sugi.bio/atlas/gene/CUX2/) |
| Protein change (HGVS p.) | p.Ala559= |
| Coding change (HGVS c.) | c.1677C>T |
| MANE Select transcript | [NM_015267](https://www.ncbi.nlm.nih.gov/nuccore/NM_015267) |
| dbSNP | [rs199689266](https://www.ncbi.nlm.nih.gov/snp/rs199689266/) |
| Variant type | single nucleotide variant |
| Location | chr12:111310459-111310459 (GRCh38) |
| ClinVar | [VCV737029](https://www.ncbi.nlm.nih.gov/clinvar/variation/737029/) |

**All HGVS expressions:** `NC_000012.11:g.111748263C>T`, `NC_000012.12:g.111310459C>T`, `NG_023039.2:g.281436C>T`, `NM_001370598.1:c.1491C>T`, `NM_015267.4:c.1677C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.25) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -3.425, GERP -2.26 — fast-evolving / accelerated position
- CADD: **PHRED 11.48**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.25**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.25**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.033%** (mid) · FAF95 0.0108% · FAF99 0.0102% · 2/6,066 in the highest group · 165/1,613,480 alleles overall — ultra-rare (popmax 0.033%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.033% | 3,033 |
| European (non-Finnish) | 0.0125% | 8,027 |
| Admixed American | 0.0117% | 8,573 |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,925 |
| Finnish (not grpmax-eligible) | 0.00158% | 63,470 |
| African / African-American | 0.00133% | 74,952 |

*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}

**CUX2** population constraint: LOEUF 0.383, pLI 1, missense-Z 2.1579. *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):

- **genetic developmental and epileptic encephalopathy** — Moderate (AD)

## Protein context {#protein}

Residue **559** lies in a DNA-binding region; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 60.99, 25% of residues very-high.

**3 experimental structure(s)** (PDB): [1WH6](https://www.rcsb.org/structure/1WH6), [1WH8](https://www.rcsb.org/structure/1WH8), [1X2L](https://www.rcsb.org/structure/1X2L).

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

*Describes the biological roles of CUX2 (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:** CUX2's established molecular role includes sequence-specific DNA binding. p.Ala559= falls in a DNA-binding region.


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

**Molecular function:** sequence-specific DNA binding, sequence-specific double-stranded DNA binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, cognition.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-06-01.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2019–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2019-12-31 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-06-01 |

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

## Similar variants {#similar}

Related CUX2 variant pages (same residue, condition, or type): [CUX2 p.Glu590Lys](/variant/cux2-p-glu590lys), [CUX2 p.Ala302Ser](/variant/cux2-p-ala302ser), [CUX2 p.Ala336Thr](/variant/cux2-p-ala336thr), [CUX2 p.Ala544Val](/variant/cux2-p-ala544val), [CUX2 p.Arg312Gln](/variant/cux2-p-arg312gln), [CUX2 p.Arg599Ser](/variant/cux2-p-arg599ser), [CUX2 p.Arg701His](/variant/cux2-p-arg701his), [CUX2 p.Arg903His](/variant/cux2-p-arg903his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 737029). 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.*