# NM_014412.3(CACYBP):c.21G>C (p.Gln7His)

https://sugi.bio/variant/cacybp-p-gln7his

## Summary

**CACYBP p.Gln7His (c.21G>C)** is classified **Uncertain significance** in CACYBP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: likely benign (0.3041); Very rare (popmax 0.000171%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.000171%, nfe)

## For patients & families {#patients}

This is a change in the CACYBP 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 | [CACYBP](https://sugi.bio/atlas/gene/CACYBP/) |
| Protein change (HGVS p.) | p.Gln7His |
| Coding change (HGVS c.) | c.21G>C |
| MANE Select transcript | [NM_014412](https://www.ncbi.nlm.nih.gov/nuccore/NM_014412) |
| Variant type | single nucleotide variant |
| Location | chr1:175004619-175004619 (GRCh38) |
| ClinVar | [VCV4218120](https://www.ncbi.nlm.nih.gov/clinvar/variation/4218120/) |

**All HGVS expressions:** `NC_000001.10:g.174973755G>C`, `NC_000001.11:g.175004619G>C`, `NG_029961.1:g.10185G>C`, `NG_029961.2:g.10186G>C`, `NM_001007214.1:c.-109G>C`, `NM_014412.3:c.21G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.3041)
- REVEL 0.218 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.367 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.25) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.933, GERP 1.7, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.2**. 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 0.63** across the covering region of the MANE Select transcript (175,000,181–175,010,076), spanning 9,895 bp. Chi-square p 1.4e-09. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.25**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 1 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.000171%** (nfe) · FAF95 2.9e-05% · FAF99 1.1e-05% · 2/1,167,036 in the highest group · 2/1,430,676 alleles overall — very rare (popmax 0.000171%, 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}

**CACYBP** population constraint: LOEUF 1.441, pLI 0.0070348, missense-Z 0.80172. *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 **7** lies in an α-helix; the 'interaction with siah1' region.

AlphaFold model confidence (whole protein): pLDDT 82.05, 55% of residues very-high.

**3 experimental structure(s)** (PDB): [1X5M](https://www.rcsb.org/structure/1X5M), [2A25](https://www.rcsb.org/structure/2A25), [2A26](https://www.rcsb.org/structure/2A26).

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

*Describes the biological roles of CACYBP (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:** CACYBP's established molecular role includes protein homodimerization activity. p.Gln7His falls in the interaction with siah1 region.


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

**Molecular function:** protein homodimerization activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-05.

**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 | 2025-08-05 |

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

## Similar variants {#similar}

Related CACYBP variant pages (same residue, condition, or type): [CACYBP p.Thr109=](/variant/cacybp-p-thr109), [CACYBP p.Arg208Gln](/variant/cacybp-p-arg208gln), [CACYBP p.Arg26Gly](/variant/cacybp-p-arg26gly), [CACYBP p.Glu184Gly](/variant/cacybp-p-glu184gly), [CACYBP p.Glu227Gly](/variant/cacybp-p-glu227gly), [CACYBP p.Ile152Thr](/variant/cacybp-p-ile152thr), [CACYBP p.Leu120Pro](/variant/cacybp-p-leu120pro), [CACYBP p.Leu55Phe](/variant/cacybp-p-leu55phe).

### 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 4218120). 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.*