Is MLH3 p.Pro87Arg (c.260C>G) pathogenic?

MLH3 p.Pro87Arg (c.260C>G) is classified Uncertain significance in MLH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-09). AlphaMissense: ambiguous (0.3722); Absent from gnomAD v4.1; Associated with colorectal cancer, hereditary nonpolyposis, type 7.

What condition is associated with MLH3 p.Pro87Arg (c.260C>G)?

MLH3 p.Pro87Arg (c.260C>G) is associated with colorectal cancer, hereditary nonpolyposis, type 7 (ClinVar).

How common is MLH3 p.Pro87Arg (c.260C>G) in the general population?

MLH3 p.Pro87Arg (c.260C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MLH3 p.Pro87Arg (c.260C>G)?

AlphaMissense predicts ambiguous (score 0.3722) — an in-silico prediction, not a clinical call.

MLH3 p.Pro87Arg

c.260C>G · rs749968114 · VCV2844391

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3722 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

colorectal cancer, hereditary nonpolyposis, type 7

Computational evidence

Protein change
AlphaMissense	0.3722	ambiguous
REVEL	0.33	indeterminate
SaProt	LLR -10.18	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 33 kb · p 2.3e-05 · regional, not allelic
Overall
CADD	23.1	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: MLH3
Protein: p.Pro87Arg
Coding: c.260C>G
MANE Select: NM_001040108
dbSNP: rs749968114
Type: single nucleotide variant
Location: chr14:75049396 (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.Pro87Leu Uncertain significance ★★ ⚠ same residue
MLH3 p.Pro87Ala Uncertain significance ★ ⚠ same residue
MLH3 p.Pro87Ser 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

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-pro87arg (accessed [today's date]).

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