MLPH p.Leu227=
c.681C>T · rs2292881 · VCV1247906
Benign
Multiple submitters
Classification
Benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Common
common (popmax 20.8%, sas) — too common for a highly-penetrant pathogenic allele
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| REVEL | 0.013 | strongly benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | Δ0.25 | acceptor gain · deltas |
| Constraint at this position | ||
| Conservation | phyloP 1.2 | GERP 1.1, phastCons 0.61 |
| Overall | ||
| CADD | 8.493 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
20.8%
South Asian · 18,940/91,058 alleles
Filtering AF
20.6%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 20.4%
Overall
9.97%
160,910/1,613,796 alleles · common
exomes 145,645/1,461,566 · genomes 15,265/152,230 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 20.8% | 5 |
| Admixed American | 20.1% | 5 |
| East Asian | 19.8% | 5 |
| Middle Eastern | 16% | 6 |
| Ashkenazi Jewishnot grpmax-eligible | 12.3% | 8 |
| Remaining individualsnot grpmax-eligible | 11.1% | 9 |
| African / African-American | 8.69% | 12 |
| European (non-Finnish) | 8.39% | 12 |
| Finnishnot grpmax-eligible | 6.08% | 16 |
| Amishnot grpmax-eligible | 5.04% | 20 |
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
- MLPH
- Protein
- p.Leu227=
- Coding
- c.681C>T
- MANE Select
- NM_024101
- dbSNP
- rs2292881
- Type
- single nucleotide variant
- Location
- chr2:237525606 (GRCh38)
- Gene constraint
- LOEUF 0.856 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 61.58
- Residue 227
- the 'disordered' region
Similar variants
- MLPH p.Arg35Gln Pathogenic/Likely pathogenic ★★ same type
- MLPH p.Arg35Trp Pathogenic/Likely pathogenic ★★ same type
- MLPH p.Ala236Thr Uncertain significance ★★ ⚠ same type
- MLPH p.Ala520Ser Uncertain significance ★★ ⚠ same type
- MLPH p.Arg375Cys Uncertain significance ★★ ⚠ same type
- MLPH p.Arg507Trp Uncertain significance ★★ ⚠ same type
- MLPH p.Arg518Gly Uncertain significance ★★ ⚠ same type
- MLPH p.Asp194Asn Uncertain significance ★★ ⚠ 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/mlph-p-leu227 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown