Is MLH1 p.Pro290Ser (c.868C>T) pathogenic?

MLH1 p.Pro290Ser (c.868C>T) is classified Uncertain significance in MLH1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-11). AlphaMissense: likely pathogenic (0.7966); Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MLH1 p.Pro290Ser (c.868C>T)?

MLH1 p.Pro290Ser (c.868C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MLH1 p.Pro290Ser (c.868C>T) in the general population?

MLH1 p.Pro290Ser (c.868C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about MLH1 p.Pro290Ser (c.868C>T)?

AlphaMissense predicts likely pathogenic (score 0.7966) — an in-silico prediction, not a clinical call.

MLH1 p.Pro290Ser

c.868C>T · rs1553646744 · VCV1478001

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7966 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.7966	likely pathogenic
REVEL	0.886	moderately pathogenic-leaning
SaProt	LLR -10.26	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 57 kb · p 0.11 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,674 alleles

Overall 6.2e-05% 1/1,613,736 alleles · very rare exomes 1/1,461,486 · genomes 0/152,250 · joint denominator

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: MLH1
Protein: p.Pro290Ser
Coding: c.868C>T
MANE Select: NM_000249
dbSNP: rs1553646744
Type: single nucleotide variant
Location: chr3:37017583 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 290: a UniProt-annotated variant site (in lynch2)

Full MLH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MLH1 p.Pro290Ala Uncertain significance ★★ ⚠ same residue
MLH1 p.Pro290= Likely benign ★ same residue
MLH1 p.Pro290fs Pathogenic ★ same residue
MLH1 c.1039-1G>A Pathogenic ★★★ same condition
MLH1 c.1039-2A>T Likely pathogenic ★★★ same condition
MLH1 c.116+1G>A Likely pathogenic ★★★ same condition
MLH1 c.116+5G>C Pathogenic ★★★ same condition
MLH1 c.117-1G>T Likely pathogenic ★★★ 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/mlh1-p-pro290ser (accessed [today's date]).

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