PHC1 p.Val73Ile
c.217G>A · VCV4567319
Computational evidence
| Protein change | ||
| AlphaMissense | 0.2903 | likely benign |
|---|---|---|
| REVEL | 0.181 | moderately benign-leaning |
| SaProt | LLR -6.83 | tolerated |
| ⇒ AlphaMissense, REVEL and SaProt all call this tolerated. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 1.7, phastCons 1 |
| Regional constraint | o/e 0.72 | unconstrained · MANE · 13 kb · p 2.3e-07 · regional, not allelic |
| Overall | ||
| CADD | 29.9 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Remaining individualsnot grpmax-eligible | 0.00162% | 61,810 |
| African / African-Americangrpmax | 0.00134% | 74,804 |
| South Asian | 0.00113% | 88,742 |
| European (non-Finnish) | 0.00103% | 97,508 |
Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
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
- PHC1
- Protein
- p.Val73Ile
- Coding
- c.217G>A
- MANE Select
- NM_004426
- Type
- single nucleotide variant
- Location
- chr12:8919858 (GRCh38)
- Gene constraint
- LOEUF 0.322 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 51.06 · 1 PDB
Similar variants
- PHC1 p.Val73= Likely benign same residue
- PHC1 p.Arg876Gln Uncertain significance ★★ ⚠ same type
- PHC1 p.Arg876Trp Uncertain significance ★★ ⚠ same type
- PHC1 p.Arg939His Uncertain significance ★★ ⚠ same type
- PHC1 p.Glu684Ala Uncertain significance ★★ ⚠ same type
- PHC1 p.His629Asn Uncertain significance ★★ ⚠ same type
- PHC1 c.1106-60G>A Benign ★★ same type
- PHC1 c.114+191T>C Benign ★★ 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/phc1-p-val73ile (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown