Is MLH3 p.Pro515fs (c.1544del) pathogenic?

MLH3 p.Pro515fs (c.1544del) is classified Conflicting classifications of pathogenicity in MLH3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-06-03). Very rare (popmax 0.000424%, nfe); Associated with colorectal cancer, hereditary nonpolyposis, type 7.

What condition is associated with MLH3 p.Pro515fs (c.1544del)?

MLH3 p.Pro515fs (c.1544del) is associated with colorectal cancer, hereditary nonpolyposis, type 7 (ClinVar).

How common is MLH3 p.Pro515fs (c.1544del) in the general population?

MLH3 p.Pro515fs (c.1544del) is very rare (popmax 0.000424%, nfe) (gnomAD).

MLH3 p.Pro515fs

c.1544del · rs1483695119 · VCV2073049

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000424%, 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.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.18	GERP -1.1
Overall
CADD	17.36	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,180,026 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,070 alleles · very rare

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.Pro515fs
Coding: c.1544del
MANE Select: NM_001040108
dbSNP: rs1483695119
Type: Deletion
Location: chr14:75048112 (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.Pro515= Likely benign ★★ same residue
MLH3 p.Ala42fs Pathogenic/Likely pathogenic ★★ same condition
MLH3 p.Glu301fs Pathogenic ★★ same condition
MLH3 p.Gly1319fs Pathogenic/Likely pathogenic ★★ same condition
MLH3 p.Gly62fs Pathogenic ★★ same condition
MLH3 p.Ile328fs Likely pathogenic ★★ same condition
MLH3 p.Ile995fs 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-pro515fs (accessed [today's date]).

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