MLH3 p.Pro1398=
c.4194T>C · rs1304593902 · VCV1626708
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0983%, amr)
Conditions
1
colorectal cancer, hereditary nonpolyposis, type 7
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.016 | strongly benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP -3.4 | GERP -3.5 |
| Overall | ||
| CADD | 0.694 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0983%
Admixed American · 59/60,006 alleles
Filtering AF
0.0782%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0709%
Overall
0.00415%
67/1,614,082 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.0983% | 1,017 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,484 |
| European (non-Finnish) | 0.000593% | 168,575 |
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
- MLH3
- Protein
- p.Pro1398=
- Coding
- c.4194T>C
- MANE Select
- NM_001040108
- dbSNP
- rs1304593902
- Type
- single nucleotide variant
- Location
- chr14:75018877 (GRCh38)
- Gene constraint
- LOEUF 0.735 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 56.14
Similar variants
- MLH3 p.Pro1398Leu Uncertain significance ★★ ⚠ same residue
- MLH3 p.Pro1398Ser Uncertain significance ★★ ⚠ same residue
- MLH3 p.Gln1360Ter Pathogenic ★★ same condition
- MLH3 p.Gln423Ter Pathogenic ★★ same condition
- MLH3 p.Ser626Ter Pathogenic ★★ same condition
- MLH3 p.Tyr441Ter Pathogenic ★★ same condition
- MLH3 c.3280+4A>G Uncertain significance ★★ same condition
- MLH3 c.3379+4A>G Uncertain significance ★★ 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/mlh3-p-pro1398 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown