# NM_145200.5(CABP4):c.66dup (p.Ala23fs)

https://sugi.bio/variant/cabp4-p-ala23fs

## Summary

**CABP4 p.Ala23fs (c.66dup)** is classified **Pathogenic** in CABP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-10). Very rare (popmax 8.49e-05%, nfe).

**At a glance:** Pathogenic · review: Single submitter · rsID rs1864734117 · 1 submitter · very rare (popmax 8.49e-05%, nfe)

## For patients & families {#patients}

This is a change in the CABP4 gene that is reported as disease-causing, but on limited review, 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 | [CABP4](https://sugi.bio/atlas/gene/CABP4/) |
| Protein change (HGVS p.) | p.Ala23fs |
| Coding change (HGVS c.) | c.66dup |
| MANE Select transcript | [NM_145200](https://www.ncbi.nlm.nih.gov/nuccore/NM_145200) |
| dbSNP | [rs1864734117](https://www.ncbi.nlm.nih.gov/snp/rs1864734117/) |
| Variant type | Duplication |
| Location | chr11:67455488-67455489 (GRCh38) |
| ClinVar | [VCV1383967](https://www.ncbi.nlm.nih.gov/clinvar/variation/1383967/) |

**All HGVS expressions:** `NC_000011.10:g.67455489dup`, `NC_000011.9:g.67222960dup`, `NG_021211.1:g.5143dup`, `NM_001300895.3:c.-318dup`, `NM_001300896.3:c.-112-220dup`, `NM_001379183.1:c.-332dup`, `NM_145200.5:c.66dup`, `NR_166529.1:n.136dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 2.101, GERP 0.701, phastCons 0.007 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.345, pLI 8.2977e-11. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 6**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.49e-05%** (nfe) · 1/1,178,522 in the highest group · 2/1,456,526 alleles overall — very rare (popmax 8.49e-05%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,296 |
| European (non-Finnish) (grpmax) | 8.49e-05% | 1,178,523 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**CABP4** population constraint: LOEUF 1.345, pLI 8.2977e-11, missense-Z -0.65326; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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 **23** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 65.01, 1% of residues very-high.

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

*Describes the biological roles of CABP4 (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:** CABP4's established molecular role includes transmembrane transporter binding. p.Ala23fs falls in the disordered region.


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

**Molecular function:** transmembrane transporter binding.

**Biological process:** visual perception.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-03-10.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-03-10 |

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

## Similar variants {#similar}

Related CABP4 variant pages (same residue, condition, or type): [CABP4 p.Ala23Val](/variant/cabp4-p-ala23val), [CABP4 p.Ala23=](/variant/cabp4-p-ala23), [CABP4 p.Ala23Gly](/variant/cabp4-p-ala23gly), [CABP4 p.Glu153fs](/variant/cabp4-p-glu153fs), [CABP4 p.Gln9fs](/variant/cabp4-p-gln9fs), [CABP4 p.Gly121fs](/variant/cabp4-p-gly121fs), [CABP4 p.Leu198fs](/variant/cabp4-p-leu198fs), [CABP4 p.Pro114fs](/variant/cabp4-p-pro114fs).

### 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 1383967). 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.*