SHH p.Pro424=
c.1272G>A · rs1563198679 · VCV593102
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 8.7e-05%, nfe)
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 |
|---|---|---|
| Pangolin | Δ0.33 | gain · loss 0.00 · not in the SpliceAI release · independent |
| Constraint at this position | ||
| Conservation | phyloP -6.4 | GERP -2.2 |
| Overall | ||
| CADD | 1.347 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
8.7e-05%
European (non-Finnish) · 1/1,148,954 alleles
Overall
6.46e-05%
1/1,548,996 alleles · very rare
exomes 1/1,396,838 · genomes 0/152,158 · joint denominator
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.Pro424=
- Coding
- c.1272G>A
- MANE Select
- NM_000193
- dbSNP
- rs1563198679
- Type
- single nucleotide variant
- Location
- chr7:155803017 (GRCh38)
- Gene constraint
- LOEUF 0.493 · pLI 0.98 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 80.23 · 20 PDB
- Residue 424
- a UniProt-annotated variant site (in hpe3; familial)
Similar variants
- SHH p.Pro424Leu Uncertain significance ★ ⚠ same residue
- SHH p.Pro424Ala Pathogenic ⚠ same residue
- SHH c.562+1G>A Pathogenic ★★ same type
- SHH p.Arg72Ter Pathogenic ★★ same type
- SHH p.Asp222Asn Likely pathogenic ★★ same type
- SHH p.Cys198Arg Pathogenic/Likely pathogenic ★★ same type
- SHH p.Cys198Ser Likely pathogenic ★★ same type
- SHH p.Leu266Phe Likely pathogenic ★★ same type
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-pro424 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown