MLH3 p.Phe642=
c.1926T>C · rs1319967873 · VCV1129762
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
very rare (popmax 0.000508%, nfe)
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. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 7 | GERP 0.78, phastCons 1 |
| Overall | ||
| CADD | 10.51 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.000508%
European (non-Finnish) · 6/1,180,010 alleles
Filtering AF
0.000183%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00012%
Overall
0.000372%
6/1,614,142 alleles · very rare
exomes 6/1,461,828 · genomes 0/152,314 · joint denominator
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.Phe642=
- Coding
- c.1926T>C
- MANE Select
- NM_001040108
- dbSNP
- rs1319967873
- Type
- single nucleotide variant
- Location
- chr14:75047730 (GRCh38)
- Gene constraint
- LOEUF 0.735 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 56.14
- Residue 642
- the 'disordered' region
Similar variants
- MLH3 p.Phe642Cys Uncertain significance ★★ ⚠ same residue
- MLH3 p.Phe642Ser 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-phe642 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown