Is MLH3 p.Leu751= (c.2253A>G) pathogenic?

MLH3 p.Leu751= (c.2253A>G) is classified Benign/Likely benign in MLH3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-04). Very rare (popmax 0.00934%, afr); Associated with colorectal cancer, hereditary nonpolyposis, type 7.

What condition is associated with MLH3 p.Leu751= (c.2253A>G)?

MLH3 p.Leu751= (c.2253A>G) is associated with colorectal cancer, hereditary nonpolyposis, type 7 (ClinVar).

How common is MLH3 p.Leu751= (c.2253A>G) in the general population?

MLH3 p.Leu751= (c.2253A>G) is very rare (popmax 0.00934%, afr) (gnomAD).

MLH3 p.Leu751=

c.2253A>G · rs748465953 · VCV1453096

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

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 0.17	GERP -0.43, phastCons 0.99
Overall
CADD	3.261	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00934% African / African-American · 7/74,948 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000558% 9/1,614,022 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00934%	10,707
Admixed American	0.00333%	30,006

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.Leu751=
Coding: c.2253A>G
MANE Select: NM_001040108
dbSNP: rs748465953
Type: single nucleotide variant
Location: chr14:75047403 (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.Leu751Ile 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
MLH3 c.3643+2T>C 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-leu751 (accessed [today's date]).

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