NHS p.Arg231Trp
c.691C>T · rs749420963 · VCV1343031
Uncertain significance
Multiple submitters
Classification
Uncertain significance
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.023%, mid)
Conditions
1
Nance-Horan syndrome
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.116 | moderately benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 1.3 | GERP -1.4, phastCons 1 |
| Regional constraint | o/e 0.79 | unconstrained · MANE · 357 kb · p 1.3e-14 · regional, not allelic |
| Overall | ||
| CADD | 23.2 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.023%
Middle Eastern · 1/4,355 alleles
Filtering AF
0.000579%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000217%
Overall
0.000661%
8/1,210,241 alleles · ultra-rare
exomes 7/1,098,019 · genomes 1/112,222 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.023% | 4,355 |
| African / African-American | 0.00349% | 28,627 |
| European (non-Finnish) | 0.000558% | 179,055 |
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.Arg231Trp
- Coding
- c.691C>T
- MANE Select
- NM_001291867
- dbSNP
- rs749420963
- Type
- single nucleotide variant
- Location
- chrX:17687867 (GRCh38)
- Structure
- AlphaFold pLDDT 43.65
- Residue 231
- the 'wave homology domain (whd)' region
Similar variants
- NHS p.Arg231Gln Uncertain significance ★★ 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-arg231trp (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown