SMPD4 p.Phe448=
c.1344T>C · VCV4956731
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
rare (popmax 0.389%, mid)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.402 | indeterminate |
|---|---|---|
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 1.3 | phastCons 1 |
| Overall | ||
| CADD | 9.574 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.389%
Middle Eastern · 22/5,662 alleles
Filtering AF
0.263%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.226%
Overall
0.0878%
1,356/1,545,076 alleles · rare
exomes 1,354/1,393,074 · genomes 2/152,002 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.389% | 257 |
| South Asian | 0.265% | 377 |
| Finnishnot grpmax-eligible | 0.19% | 527 |
| Ashkenazi Jewishnot grpmax-eligible | 0.152% | 658 |
| European (non-Finnish) | 0.077% | 1,299 |
| Remaining individualsnot grpmax-eligible | 0.0646% | 1,547 |
| Admixed American | 0.044% | 2,275 |
| East Asian | 0.0247% | 4,051 |
| African / African-American | 0.00268% | 37,374 |
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
- SMPD4
- Protein
- p.Phe448=
- Coding
- c.1344T>C
- MANE Select
- NM_017951
- Type
- single nucleotide variant
- Location
- chr2:130155205 (GRCh38)
- Gene constraint
- LOEUF 0.769 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 72.01
- Residue 448
- a UniProt-annotated variant site (in nedmaba)
Similar variants
- SMPD4 c.1290-9G>A Pathogenic/Likely pathogenic ★★ same type
- SMPD4 c.345+1G>T Pathogenic ★★ same type
- SMPD4 p.Arg502Ter Pathogenic/Likely pathogenic ★★ same type
- SMPD4 p.Arg757Trp Uncertain significance ★★ ⚠ same type
- SMPD4 p.Gln382Glu Uncertain significance ★★ ⚠ same type
- SMPD4 p.Gln722Ter Uncertain significance ★★ same type
- SMPD4 p.Ile82Val Uncertain significance ★★ ⚠ same type
- SMPD4 c.1097+27A>G 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/smpd4-p-phe448 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown