SHH p.Pro260=
c.780G>A · rs767639456 · VCV2902943
Benign
Single submitter
Classification
Benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.05%, sas)
Conditions
1
holoprosencephaly 3
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -3.5 | GERP -4.3 |
| Overall | ||
| CADD | 10.89 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.05%
South Asian · 44/88,002 alleles
Filtering AF
0.0382%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0341%
Overall
0.00406%
64/1,578,280 alleles · ultra-rare
exomes 62/1,426,146 · genomes 2/152,134 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.05% | 2,000 |
| Middle Eastern | 0.0168% | 5,970 |
| Remaining individualsnot grpmax-eligible | 0.00489% | 20,440 |
| European (non-Finnish) | 0.00137% | 72,963 |
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
- SHH
- Protein
- p.Pro260=
- Coding
- c.780G>A
- MANE Select
- NM_000193
- dbSNP
- rs767639456
- Type
- single nucleotide variant
- Location
- chr7:155803509 (GRCh38)
- Gene constraint
- LOEUF 0.493 · pLI 0.98 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 80.23 · 20 PDB
Similar variants
- SHH p.Pro260Leu Uncertain significance ★ ⚠ same residue
- SHH p.Pro260Thr Uncertain significance ★ ⚠ same residue
- SHH p.Arg72Ter Pathogenic ★★ same condition
- SHH p.Asp222Asn Likely pathogenic ★★ same condition
- SHH p.Leu266Phe Likely pathogenic ★★ same condition
- SHH p.Leu271Pro Likely pathogenic ★★ same condition
- SHH p.Pro347Arg Likely pathogenic ★★ same condition
- SHH p.Pro347Leu Pathogenic/Likely pathogenic ★★ 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/shh-p-pro260 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown