# NM_015341.5(NCAPH):c.1786C>T (p.Pro596Ser)

https://sugi.bio/variant/ncaph-p-pro596ser

## Summary

**NCAPH p.Pro596Ser (c.1786C>T)** is classified **Uncertain significance** in NCAPH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: likely benign (0.0654); Very rare (popmax 8.47e-05%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the NCAPH 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 | [NCAPH](https://sugi.bio/atlas/gene/NCAPH/) |
| Protein change (HGVS p.) | p.Pro596Ser |
| Coding change (HGVS c.) | c.1786C>T |
| MANE Select transcript | [NM_015341](https://www.ncbi.nlm.nih.gov/nuccore/NM_015341) |
| Variant type | single nucleotide variant |
| Location | chr2:96365963-96365963 (GRCh38) |
| ClinVar | [VCV3917787](https://www.ncbi.nlm.nih.gov/clinvar/variation/3917787/) |

**All HGVS expressions:** `NC_000002.11:g.97031701C>T`, `NC_000002.12:g.96365963C>T`, `NM_001281710.2:c.1753C>T`, `NM_001281711.2:c.1714C>T`, `NM_001281712.2:c.1378C>T`, `NM_015341.5:c.1786C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0654)
- REVEL 0.073 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.486 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.113, GERP -2.86 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.929**. 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 0.86** across the covering region of the MANE Select transcript (96,335,830–96,373,348), spanning 37,518 bp. Chi-square p 2.5e-05. 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>G, Δ0.91 acceptor 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 **8.47e-05%** (nfe) · 1/1,180,036 in the highest group · 1/1,614,050 alleles overall — very rare (popmax 8.47e-05%, 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}

**NCAPH** population constraint: LOEUF 0.566, pLI 0.11118, missense-Z 1.6441. *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 60.16, 8% of residues very-high.

**1 experimental structure(s)** (PDB): [6IGX](https://www.rcsb.org/structure/6IGX).

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

*Describes the biological roles of NCAPH (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.*


### Pathways affected {#pathways}

NCAPH participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Condensation of Prometaphase Chromosomes](https://reactome.org/content/detail/R-HSA-2514853) | electronic |

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

**Biological process:** mitotic chromosome condensation, positive regulation of chromosome condensation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-06.

**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 | 2025-05-06 |

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

## Similar variants {#similar}

Related NCAPH variant pages (same residue, condition, or type): [NCAPH p.Arg451Cys](/variant/ncaph-p-arg451cys), [NCAPH c.1002+9A>G](/variant/ncaph-c-1002-plus-9a-g), [NCAPH p.Arg221Gly](/variant/ncaph-p-arg221gly), [NCAPH p.Asp377=](/variant/ncaph-p-asp377), [NCAPH p.Val384Ile](/variant/ncaph-p-val384ile), [NCAPH p.Val539Ala](/variant/ncaph-p-val539ala), [NCAPH c.19+1G>C](/variant/ncaph-c-19-plus-1g-c), [NCAPH p.Ala198Pro](/variant/ncaph-p-ala198pro).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3917787). 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.*