NHS p.Pro552Leu
c.1655C>T · rs753798177 · VCV2660085
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0229%, mid)
Conditions
1
Nance-Horan syndrome
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.064 | moderately benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 4.1 | GERP 1.9, phastCons 1 |
| Regional constraint | o/e 0.79 | unconstrained · MANE · 357 kb · p 1.3e-14 · regional, not allelic |
| Overall | ||
| CADD | 17.47 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0229%
Middle Eastern · 1/4,367 alleles
Filtering AF
0.00351%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00311%
Overall
0.00389%
47/1,209,092 alleles · ultra-rare
exomes 38/1,098,241 · genomes 9/110,851 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0229% | 4,367 |
| African / African-American | 0.00528% | 18,927 |
| European (non-Finnish) | 0.00469% | 21,311 |
| Admixed American | 0.00219% | 45,695 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- NHS
- Protein
- p.Pro552Leu
- Coding
- c.1655C>T
- MANE Select
- NM_001291867
- dbSNP
- rs753798177
- Type
- single nucleotide variant
- Location
- chrX:17725761 (GRCh38)
- Structure
- AlphaFold pLDDT 43.65
- Residue 552
- the 'disordered' region
Similar variants
- NHS p.Pro552= Likely benign ★ same residue
- NHS p.Arg248Ter Pathogenic ★★ same condition
- NHS p.Arg394Ter Pathogenic ★★ same condition
- NHS p.Arg900Ter Pathogenic ★★ same condition
- NHS p.Gln411Ter Pathogenic ★★ same condition
- NHS p.Gln80Ter Pathogenic/Likely pathogenic ★★ same condition
- NHS p.Ala564Val Uncertain significance ★★ same condition
- NHS p.Ala745Val Uncertain significance ★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/nhs-p-pro552leu (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown