# NM_015341.5(NCAPH):c.99G>T (p.Val33=)

https://sugi.bio/variant/ncaph-p-val33

## Summary

**NCAPH p.Val33= (c.99G>T)** is classified **Likely benign** in NCAPH (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-08-20). Rare (popmax 0.148%, mid); Associated with NCAPH-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs561015827 · 1 submitter · 1 linked condition · rare (popmax 0.148%, mid)

## For patients & families {#patients}

This is a change in the NCAPH gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to NCAPH-related disorder.

*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.Val33= |
| Coding change (HGVS c.) | c.99G>T |
| MANE Select transcript | [NM_015341](https://www.ncbi.nlm.nih.gov/nuccore/NM_015341) |
| dbSNP | [rs561015827](https://www.ncbi.nlm.nih.gov/snp/rs561015827/) |
| Variant type | single nucleotide variant |
| Location | chr2:96341721-96341721 (GRCh38) |
| ClinVar | [VCV3053109](https://www.ncbi.nlm.nih.gov/clinvar/variation/3053109/) |

**All HGVS expressions:** `NC_000002.11:g.97007459G>T`, `NC_000002.12:g.96341721G>T`, `NM_001281710.2:c.66G>T`, `NM_001281711.2:c.27G>T`, `NM_001281712.2:c.-136-329G>T`, `NM_015341.5:c.99G>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 0.22) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.099, GERP -2.82 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.995**. 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 **0.11**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.148%** (mid) · FAF95 0.0772% · FAF99 0.0576% · 9/6,084 in the highest group · 98/1,614,108 alleles overall — rare (popmax 0.148%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.148% | 676 |
| South Asian | 0.0154% | 6,507 |
| Remaining individuals (not grpmax-eligible) | 0.0144% | 6,943 |
| European (non-Finnish) | 0.00542% | 18,438 |
| Admixed American | 0.00333% | 30,002 |

*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}

Residue **33** lies in the 'disordered' region.

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}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-08-20.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-08-20 |

## Associated conditions {#conditions}

[NCAPH-related disorder](https://sugi.bio/atlas/disease/ncaph-related-disorder/).

**Reported phenotype names (ClinVar):** NCAPH-related disorder, NCAPH-related condition.

## Similar variants {#similar}

Related NCAPH variant pages (same residue, condition, or type): [NCAPH p.Val33Leu](/variant/ncaph-p-val33leu), [NCAPH c.2091-4C>G](/variant/ncaph-c-2091-minus-4c-g), [NCAPH c.596-4T>G](/variant/ncaph-c-596-minus-4t-g), [NCAPH c.-1G>A](/variant/ncaph-c-minus-1g-a), [NCAPH p.Asn333Ser](/variant/ncaph-p-asn333ser), [NCAPH p.Asp175=](/variant/ncaph-p-asp175), [NCAPH p.Ile99Val](/variant/ncaph-p-ile99val), [NCAPH p.Val340Ile](/variant/ncaph-p-val340ile).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 3053109). 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.*