SHH p.Arg33=
c.99G>A · VCV4734521
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00333%, amr)
Conditions
1
holoprosencephaly 3
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · C>A here scores Δ0.23 · evaluated, not missing |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 4.8 | GERP -0.086, phastCons 1 |
| Overall | ||
| CADD | 14.62 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00333%
Admixed American · 2/60,010 alleles
Filtering AF
0.000553%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000207%
Overall
0.000248%
4/1,614,046 alleles · very rare
exomes 3/1,461,878 · genomes 1/152,168 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.00333% | 30,005 |
| East Asian | 0.00223% | 44,878 |
| African / African-American | 0.00133% | 74,934 |
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.Arg33=
- Coding
- c.99G>A
- MANE Select
- NM_000193
- Type
- single nucleotide variant
- Location
- chr7:155812024 (GRCh38)
- Gene constraint
- LOEUF 0.493 · pLI 0.98 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 80.23 · 20 PDB
- Residue 33
- an α-helix
Similar variants
- SHH p.Arg33Thr 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
- SHH p.Ser436Ter 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-arg33 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown