SHH p.Pro294=
c.882T>C · rs755846157 · VCV1897453
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0426%, 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 -2.5 | GERP -2.3 |
| Overall | ||
| CADD | 5.121 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0426%
South Asian · 35/82,196 alleles
Filtering AF
0.0314%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0275%
Overall
0.00237%
36/1,518,438 alleles · ultra-rare
exomes 36/1,366,466 · genomes 0/151,972 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.0426% | 2,348 |
| Remaining individualsnot grpmax-eligible | 0.00169% | 59,032 |
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.Pro294=
- Coding
- c.882T>C
- MANE Select
- NM_000193
- dbSNP
- rs755846157
- Type
- single nucleotide variant
- Location
- chr7:155803407 (GRCh38)
- Gene constraint
- LOEUF 0.493 · pLI 0.98 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 80.23 · 20 PDB
- Residue 294
- the 'disordered' region
Similar variants
- 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
- SHH p.Ser436Ter Pathogenic/Likely pathogenic ★★ same condition
- SHH p.Tyr141Ter 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-pro294 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown