# NM_133433.4(NIPBL):c.385T>C (p.Ser129Pro)

https://sugi.bio/variant/nipbl-p-ser129pro

## Summary

**NIPBL p.Ser129Pro (c.385T>C)** is classified **Uncertain significance** in NIPBL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-22). AlphaMissense: likely benign (0.1248); Very rare (popmax 0.00267%, afr); Associated with Cornelia de Lange syndrome 1.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs141976717 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the NIPBL gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Cornelia de Lange syndrome 1.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024555/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NIPBL](https://sugi.bio/atlas/gene/NIPBL/) |
| Protein change (HGVS p.) | p.Ser129Pro |
| Coding change (HGVS c.) | c.385T>C |
| MANE Select transcript | [NM_133433](https://www.ncbi.nlm.nih.gov/nuccore/NM_133433) |
| dbSNP | [rs141976717](https://www.ncbi.nlm.nih.gov/snp/rs141976717/) |
| Variant type | single nucleotide variant |
| Location | chr5:36961510-36961510 (GRCh38) |
| ClinVar | [VCV2038735](https://www.ncbi.nlm.nih.gov/clinvar/variation/2038735/) |

**All HGVS expressions:** `NC_000005.10:g.36961510T>C`, `NC_000005.9:g.36961612T>C`, `NG_006987.2:g.89628T>C`, `NM_015384.5:c.385T>C`, `NM_133433.4:c.385T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1248)
- REVEL 0.302 (indeterminate)
- Conservation: phyloP 5.052, GERP 1.94, phastCons 1 — highly conserved (differs from AlphaMissense)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- CADD: **PHRED 21.9**. 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 0.88** across the covering region of the MANE Select transcript (36,955,570–36,976,393), spanning 20,823 bp. Chi-square p 0.0044. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for NIPBL (2,306 scored positions, the nearest 23 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.00267%** (afr) · FAF95 0.000443% · FAF99 0.00026% · 2/74,894 in the highest group · 12/1,611,334 alleles overall — very rare (popmax 0.00267%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00267% | 37,447 |
| East Asian | 0.00223% | 44,762 |
| European (non-Finnish) | 0.000764% | 130,855 |

*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}

**NIPBL** population constraint: LOEUF 0.057, pLI 1, missense-Z 6.6991; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 1/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Cornelia de Lange syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **129** lies in the 'disordered' region.

**3 experimental structure(s)** (PDB): [6WG3](https://www.rcsb.org/structure/6WG3), [6WGE](https://www.rcsb.org/structure/6WGE), [7W1M](https://www.rcsb.org/structure/7W1M).

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

*Describes the biological roles of NIPBL (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:** NIPBL's established molecular role includes transcription corepressor activity. p.Ser129Pro falls in the disordered region.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cohesin Loading onto Chromatin](https://reactome.org/content/detail/R-HSA-2470946) | curated |

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

**Molecular function:** transcription corepressor activity, histone deacetylase binding, cohesin loader activity, chromo shadow domain binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, heart morphogenesis, outflow tract morphogenesis, chromatin remodeling, DNA damage response, mitotic sister chromatid cohesion.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-01-22.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-10-25 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-22 |

## Associated conditions {#conditions}

[Cornelia de Lange syndrome 1](https://sugi.bio/atlas/disease/cornelia-de-lange-syndrome-1/).

**Reported phenotype names (ClinVar):** Cornelia de Lange syndrome 1, NIPBL-Related Cornelia de Lange Syndrome, Brachmann de Lange syndrome, TYPUS DEGENERATIVUS AMSTELODAMENSIS.

## Same-residue context {#hotspot}

Residue **129** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [NIPBL p.Ser129fs](/variant/nipbl-p-ser129fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related NIPBL variant pages (same residue, condition, or type): [NIPBL p.Ser129Cys](/variant/nipbl-p-ser129cys), [NIPBL c.3304+1G>A](/variant/nipbl-c-3304-plus-1g-a), [NIPBL c.358+1G>T](/variant/nipbl-c-358-plus-1g-t), [NIPBL c.3855+5G>A](/variant/nipbl-c-3855-plus-5g-a), [NIPBL c.5329-15A>G](/variant/nipbl-c-5329-minus-15a-g), [NIPBL c.5575-1G>A](/variant/nipbl-c-5575-minus-1g-a), [NIPBL c.5709+1G>A](/variant/nipbl-c-5709-plus-1g-a), [NIPBL c.5808+1G>A](/variant/nipbl-c-5808-plus-1g-a).

### 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 2038735). 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.*