# NM_001080503.3(CCDC159):c.134C>A (p.Ala45Asp)

https://sugi.bio/variant/ccdc159-p-ala45asp

## Summary

**CCDC159 p.Ala45Asp (c.134C>A)** is classified **Uncertain significance** in CCDC159 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-15). AlphaMissense: likely pathogenic (0.7885); Ultra-rare (popmax 0.0178%, eas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs767361219 · 1 submitter · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0178%, eas)

## For patients & families {#patients}

This is a change in the CCDC159 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 | [CCDC159](https://sugi.bio/atlas/gene/CCDC159/) |
| Protein change (HGVS p.) | p.Ala45Asp |
| Coding change (HGVS c.) | c.134C>A |
| MANE Select transcript | [NM_001080503](https://www.ncbi.nlm.nih.gov/nuccore/NM_001080503) |
| dbSNP | [rs767361219](https://www.ncbi.nlm.nih.gov/snp/rs767361219/) |
| Variant type | single nucleotide variant |
| Location | chr19:11350016-11350016 (GRCh38) |
| ClinVar | [VCV2359073](https://www.ncbi.nlm.nih.gov/clinvar/variation/2359073/) |

**All HGVS expressions:** `NC_000019.10:g.11350016C>A`, `NC_000019.9:g.11460692C>A`, `NM_001080503.3:c.134C>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.7885)
- REVEL 0.171 (moderately benign-leaning) — differs from AlphaMissense
- SaProt LLR -6.631 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- Conservation: phyloP 7.288, GERP 2.12, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 9%** most-pathogenic-predicted substitutions in CCDC159 (of 1,732 modeled).
- CADD: **PHRED 27.4**. 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 0.96** across the covering region of the MANE Select transcript (11,346,607–11,354,874), spanning 8,267 bp. Chi-square p 0.42. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.26 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 **0.0178%** (eas) · FAF95 0.00884% · FAF99 0.00641% · 8/44,862 in the highest group · 16/1,613,704 alleles overall — ultra-rare (popmax 0.0178%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0178% | 5,608 |
| South Asian | 0.00549% | 18,215 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,241 |
| European (non-Finnish) | 8.48e-05% | 1,179,786 |

*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}

**CCDC159** population constraint: LOEUF 1.11, pLI 1.1724e-11, missense-Z -0.35993. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 77.97, 54% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-07-15.

**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 | 2021-07-15 |

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

## Similar variants {#similar}

Related CCDC159 variant pages (same residue, condition, or type): [CCDC159 p.Ala203Thr](/variant/ccdc159-p-ala203thr), [CCDC159 p.Arg117Cys](/variant/ccdc159-p-arg117cys), [CCDC159 p.Arg117His](/variant/ccdc159-p-arg117his), [CCDC159 p.Arg124Trp](/variant/ccdc159-p-arg124trp), [CCDC159 p.Arg126Gly](/variant/ccdc159-p-arg126gly), [CCDC159 p.Arg139Gln](/variant/ccdc159-p-arg139gln), [CCDC159 p.Arg139Trp](/variant/ccdc159-p-arg139trp), [CCDC159 p.Arg153Gln](/variant/ccdc159-p-arg153gln).

### 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 2359073). 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.*