SHH p.Phe252=
c.756C>T · rs113275997 · VCV787852
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 4 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0642%, afr)
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 4.5 | GERP -2.8, phastCons 1 |
| Overall | ||
| CADD | 11.85 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0642%
African / African-American · 48/74,788 alleles
Filtering AF
0.0496%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0445%
Overall
0.00314%
50/1,593,238 alleles · ultra-rare
exomes 20/1,441,080 · genomes 30/152,158 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.0642% | 1,558 |
| Admixed American | 0.00169% | 59,058 |
| Remaining individualsnot grpmax-eligible | 0.00161% | 61,972 |
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.Phe252=
- Coding
- c.756C>T
- MANE Select
- NM_000193
- dbSNP
- rs113275997
- Type
- single nucleotide variant
- Location
- chr7:155803533 (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.Phe252del Uncertain significance ★ same residue
- SHH p.Phe252Ser 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-phe252 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown