# NM_001291867.2(NHS):c.567C>T (p.Pro189=)

https://sugi.bio/variant/nhs-p-pro189

## Summary

**NHS p.Pro189= (c.567C>T)** is classified **Likely benign** in NHS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-10). Very rare (popmax 0.00536%, nfe); Associated with Nance-Horan syndrome.

**At a glance:** Likely benign · review: Single submitter · rsID rs972522687 · 1 submitter · 1 linked condition · very rare (popmax 0.00536%, nfe)

## For patients & families {#patients}

This is a change in the NHS gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Nance-Horan syndrome.

*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/0007161/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NHS](https://sugi.bio/atlas/gene/NHS/) |
| Protein change (HGVS p.) | p.Pro189= |
| Coding change (HGVS c.) | c.567C>T |
| MANE Select transcript | [NM_001291867](https://www.ncbi.nlm.nih.gov/nuccore/NM_001291867) |
| dbSNP | [rs972522687](https://www.ncbi.nlm.nih.gov/snp/rs972522687/) |
| Variant type | single nucleotide variant |
| Location | chrX:17687743-17687743 (GRCh38) |
| ClinVar | [VCV2893442](https://www.ncbi.nlm.nih.gov/clinvar/variation/2893442/) |

**All HGVS expressions:** `NC_000023.10:g.17705863C>T`, `NC_000023.11:g.17687743C>T`, `NG_011553.2:g.317324C>T`, `NM_001136024.4:c.36C>T`, `NM_001291867.2:c.567C>T`, `NM_001291868.2:c.36C>T`, `NM_198270.4:c.567C>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 (below), not from a missing predictor score.
- Conservation: phyloP -8.045, GERP -3.81 — fast-evolving / accelerated position
- CADD: **PHRED 0.111**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.76 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 **0.00536%** (nfe) · FAF95 0.00415% · FAF99 0.00367% · 48/895,479 in the highest group · 50/1,211,914 alleles overall — very rare (popmax 0.00536%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00536% | 18,656 |
| Remaining individuals (not grpmax-eligible) | 0.0042% | 23,828 |

*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}

**NHS** population constraint: ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **Nance-Horan syndrome** — Definitive (XL)

## Protein context {#protein}

Residue **189** lies in the 'wave homology domain (whd)' region.

AlphaFold model confidence (whole protein): pLDDT 43.65, 4% of residues very-high.

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

*Describes the biological roles of NHS (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}

NHS participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | curated |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | curated |

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-02-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-02-10 |

## Associated conditions {#conditions}

[Nance-Horan syndrome](https://sugi.bio/atlas/disease/nance-horan-syndrome/).

**Reported phenotype names (ClinVar):** Nance-Horan syndrome.

## Similar variants {#similar}

Related NHS variant pages (same residue, condition, or type): [NHS p.Arg248Ter](/variant/nhs-p-arg248ter), [NHS p.Arg394Ter](/variant/nhs-p-arg394ter), [NHS p.Arg900Ter](/variant/nhs-p-arg900ter), [NHS p.Gln411Ter](/variant/nhs-p-gln411ter), [NHS p.Gln80Ter](/variant/nhs-p-gln80ter), [NHS p.Ala564Val](/variant/nhs-p-ala564val), [NHS p.Ala745Val](/variant/nhs-p-ala745val), [NHS p.Arg162Cys](/variant/nhs-p-arg162cys).

### 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 2893442). 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.*