Is MLH3 p.Pro515= (c.1545A>G) pathogenic?

MLH3 p.Pro515= (c.1545A>G) is classified Likely benign in MLH3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-19). Very rare (popmax 8.47e-05%, nfe); Associated with colorectal cancer, hereditary nonpolyposis, type 7.

What condition is associated with MLH3 p.Pro515= (c.1545A>G)?

MLH3 p.Pro515= (c.1545A>G) is associated with colorectal cancer, hereditary nonpolyposis, type 7 (ClinVar).

How common is MLH3 p.Pro515= (c.1545A>G) in the general population?

MLH3 p.Pro515= (c.1545A>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

MLH3 p.Pro515=

c.1545A>G · rs2503292582 · VCV1774911

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.18	GERP -1.1
Overall
CADD	0.896	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,018 alleles

Overall 6.2e-05% 1/1,614,188 alleles · very rare exomes 1/1,461,816 · genomes 0/152,372 · 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.Pro515=
Coding: c.1545A>G
MANE Select: NM_001040108
dbSNP: rs2503292582
Type: single nucleotide variant
Location: chr14:75048111 (GRCh38)
Gene constraint: LOEUF 0.735 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 56.14

Full MLH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

colorectal cancer, hereditary nonpolyposis, type 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MLH3 p.Pro515Leu Uncertain significance ★★ ⚠ same residue
MLH3 p.Pro515fs Conflicting classifications of pathogenicity ★ same residue
MLH3 p.Pro515Arg Uncertain significance ★ ⚠ same residue
MLH3 p.Pro515Thr 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

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-pro515 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown