Is MLH3 p.Ser110= (c.330G>A) pathogenic?

MLH3 p.Ser110= (c.330G>A) is classified Benign/Likely benign in MLH3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-04-28). Rare (popmax 0.12%, sas); Associated with colorectal cancer, hereditary nonpolyposis, type 7.

What condition is associated with MLH3 p.Ser110= (c.330G>A)?

MLH3 p.Ser110= (c.330G>A) is associated with colorectal cancer, hereditary nonpolyposis, type 7, endometrial carcinoma, colorectal cancer (ClinVar).

How common is MLH3 p.Ser110= (c.330G>A) in the general population?

MLH3 p.Ser110= (c.330G>A) is rare (popmax 0.12%, sas) (gnomAD).

MLH3 p.Ser110=

c.330G>A · rs189749330 · VCV416459

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.12%, sas)

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 0.13	GERP -3.2, phastCons 0.99
Overall
CADD	5.525	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.12% South Asian · 109/91,082 alleles

Filtering AF 0.101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0946%

Overall 0.00948% 153/1,614,102 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.12%	836
African / African-American	0.00533%	18,759
Admixed American	0.005%	20,007
Remaining individualsnot grpmax-eligible	0.0048%	20,837
European (non-Finnish)	0.00288%	34,707

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.Ser110=
Coding: c.330G>A
MANE Select: NM_001040108
dbSNP: rs189749330
Type: single nucleotide variant
Location: chr14:75049326 (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

Also linked: endometrial carcinoma colorectal cancer

Similar variants

MLH3 p.Ser110Leu Uncertain significance ★★ ⚠ same residue
MLH3 p.Ser110Ter Pathogenic ★ same residue
MLH3 p.Ser110Ala 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-ser110 (accessed [today's date]).

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