Is MLH3 p.Ser490Pro (c.1468T>C) pathogenic?

MLH3 p.Ser490Pro (c.1468T>C) is classified Uncertain significance in MLH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-19). AlphaMissense: likely benign (0.0739); Absent from gnomAD v4.1; Associated with colorectal cancer, hereditary nonpolyposis, type 7.

What condition is associated with MLH3 p.Ser490Pro (c.1468T>C)?

MLH3 p.Ser490Pro (c.1468T>C) is associated with colorectal cancer, hereditary nonpolyposis, type 7 (ClinVar).

How common is MLH3 p.Ser490Pro (c.1468T>C) in the general population?

MLH3 p.Ser490Pro (c.1468T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MLH3 p.Ser490Pro (c.1468T>C)?

AlphaMissense predicts likely benign (score 0.0739) — an in-silico prediction, not a clinical call.

MLH3 p.Ser490Pro

c.1468T>C · rs759885152 · VCV1003436

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0739 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

colorectal cancer, hereditary nonpolyposis, type 7

Computational evidence

Protein change
AlphaMissense	0.0739	likely benign
REVEL	0.244	benign-leaning
SaProt	LLR -7.06	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.57	GERP -2.3
Regional constraint	o/e 0.90	unconstrained · MANE · 33 kb · p 2.3e-05 · regional, not allelic
Overall
CADD	7.908	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.Ser490Pro
Coding: c.1468T>C
MANE Select: NM_001040108
dbSNP: rs759885152
Type: single nucleotide variant
Location: chr14:75048188 (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.Ser490fs Uncertain significance ★ same residue
MLH3 p.Ser490= Likely benign ★ 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-ser490pro (accessed [today's date]).

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