Is MLH3 p.Pro1109Ser (c.3325C>T) pathogenic?

MLH3 p.Pro1109Ser (c.3325C>T) is classified Uncertain significance in MLH3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-27). AlphaMissense: ambiguous (0.5106); Very rare (popmax 0.00186%, nfe); Associated with colorectal cancer, hereditary nonpolyposis, type 7.

What condition is associated with MLH3 p.Pro1109Ser (c.3325C>T)?

MLH3 p.Pro1109Ser (c.3325C>T) is associated with colorectal cancer, hereditary nonpolyposis, type 7 (ClinVar).

How common is MLH3 p.Pro1109Ser (c.3325C>T) in the general population?

MLH3 p.Pro1109Ser (c.3325C>T) is very rare (popmax 0.00186%, nfe) (gnomAD).

What do computational predictors say about MLH3 p.Pro1109Ser (c.3325C>T)?

AlphaMissense predicts ambiguous (score 0.5106) — an in-silico prediction, not a clinical call.

MLH3 p.Pro1109Ser

c.3325C>T · rs140997957 · VCV1469302

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5106 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00186%, nfe)

Conditions

colorectal cancer, hereditary nonpolyposis, type 7

Computational evidence

Protein change
AlphaMissense	0.5106	ambiguous
REVEL	0.625	indeterminate
SaProt	LLR -5.95	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 33 kb · p 2.3e-05 · regional, not allelic
Overall
CADD	27.4	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

Grpmax group 0.00186% European (non-Finnish) · 22/1,180,038 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00149% 24/1,614,076 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00186%	53,638
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-American	0.00133%	74,934

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.Pro1109Ser
Coding: c.3325C>T
MANE Select: NM_001040108
dbSNP: rs140997957
Type: single nucleotide variant
Location: chr14:75042433 (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.Pro1109Arg Uncertain significance ★ ⚠ same residue
MLH3 p.Pro1109His Uncertain significance ★ ⚠ same residue
MLH3 p.Pro1109Leu 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-pro1109ser (accessed [today's date]).

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