MLH1 p.Gln537Pro
c.1610A>C · VCV4961662
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
AlphaMissense
ambiguous
0.4195 · ACMG-weighted
gnomAD v4.1
Absent
absent from gnomAD v4.1
Missense predictors
2/2 damaging
REVEL, SaProt · AlphaMissense indeterminate
Computational evidence
| Protein change | ||
| AlphaMissense | 0.4195 | ambiguous |
|---|---|---|
| REVEL | 0.801 | moderately pathogenic-leaning |
| SaProt | LLR -11.99 | damaging |
| ⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 9.4 | GERP 1, phastCons 1 |
| Regional constraint | o/e 0.95 | unconstrained · MANE · 57 kb · p 0.11 · regional, not allelic |
| Overall | ||
| CADD | 25.1 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
gnomAD v4.1 · exomes + genomes
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- MLH1
- Protein
- p.Gln537Pro
- Coding
- c.1610A>C
- MANE Select
- NM_000249
- Type
- single nucleotide variant
- Location
- chr3:37040237 (GRCh38)
- Gene constraint
- LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 77.89 · 13 PDB
- Residue 537
- a β-strand; the 'interaction with exo1' region
Similar variants
- MLH1 p.Gln537Ter Pathogenic ★★★ same residue
- MLH1 p.Gln537Leu Uncertain significance ★★ ⚠ same residue
- MLH1 p.Gln537= Benign/Likely benign ★★ same residue
- MLH1 p.Gln537His Uncertain significance ★ ⚠ same residue
- MLH1 p.Gln537fs Pathogenic ★★ same residue
- MLH1 p.Gln537delinsValTer Pathogenic ★ same residue
- MLH1 c.1038+1G>C Likely pathogenic ★★★ same type
- MLH1 c.1039-1G>A Pathogenic ★★★ 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/mlh1-p-gln537pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown