Is MLH3 p.Pro1449= (c.4347C>T) pathogenic?

MLH3 p.Pro1449= (c.4347C>T) is classified Likely benign in MLH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-02). Absent from gnomAD v4.1; Associated with colorectal cancer, hereditary nonpolyposis, type 7.

What condition is associated with MLH3 p.Pro1449= (c.4347C>T)?

MLH3 p.Pro1449= (c.4347C>T) is associated with colorectal cancer, hereditary nonpolyposis, type 7 (ClinVar).

How common is MLH3 p.Pro1449= (c.4347C>T) in the general population?

MLH3 p.Pro1449= (c.4347C>T) is absent from gnomAD v4.1 (gnomAD).

MLH3 p.Pro1449=

c.4347C>T · rs2139282721 · VCV1577116

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

colorectal cancer, hereditary nonpolyposis, type 7

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.111	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.28	GERP -3.2, phastCons 0.001
Overall
CADD	1.56	PHRED · no single calibrated threshold — expert panels disagree

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: MLH3
Protein: p.Pro1449=
Coding: c.4347C>T
MANE Select: NM_001040108
dbSNP: rs2139282721
Type: single nucleotide variant
Location: chr14:75017097 (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.Pro1449Arg Uncertain significance ★ ⚠ same residue
MLH3 p.Pro1449Leu 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-pro1449 (accessed [today's date]).

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