Is MLH3 p.Ser287= (c.861T>C) pathogenic?

MLH3 p.Ser287= (c.861T>C) is classified Benign/Likely benign in MLH3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-04-29). Ultra-rare (popmax 0.0119%, nfe); Associated with colorectal cancer, hereditary nonpolyposis, type 7.

What condition is associated with MLH3 p.Ser287= (c.861T>C)?

MLH3 p.Ser287= (c.861T>C) is associated with colorectal cancer, hereditary nonpolyposis, type 7 (ClinVar).

How common is MLH3 p.Ser287= (c.861T>C) in the general population?

MLH3 p.Ser287= (c.861T>C) is ultra-rare (popmax 0.0119%, nfe) (gnomAD).

MLH3 p.Ser287=

c.861T>C · rs201745687 · VCV544289

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0119%, nfe)

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 2.3	GERP -0.57, phastCons 0.9
Overall
CADD	1.641	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0119% European (non-Finnish) · 141/1,180,028 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00972%

Overall 0.00886% 143/1,614,050 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0119%	8,369
Remaining individualsnot grpmax-eligible	0.0032%	31,243

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.Ser287=
Coding: c.861T>C
MANE Select: NM_001040108
dbSNP: rs201745687
Type: single nucleotide variant
Location: chr14:75048795 (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.Ser287fs Likely pathogenic ★ same residue
MLH3 p.Ser287Asn Uncertain significance ★ ⚠ same residue
MLH3 p.Ser287Thr 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-ser287 (accessed [today's date]).

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