Is MLH1 p.Pro403Ser (c.1207C>T) pathogenic?

MLH1 p.Pro403Ser (c.1207C>T) is classified Conflicting classifications of pathogenicity in MLH1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-07-20). AlphaMissense: likely benign (0.0686); Very rare (popmax 0.000254%, nfe); Associated with Lynch syndrome 2.

What condition is associated with MLH1 p.Pro403Ser (c.1207C>T)?

MLH1 p.Pro403Ser (c.1207C>T) is associated with Lynch syndrome 2, Muir-Torre syndrome, hereditary neoplastic syndrome (ClinVar).

How common is MLH1 p.Pro403Ser (c.1207C>T) in the general population?

MLH1 p.Pro403Ser (c.1207C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

How is Lynch syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MLH1 p.Pro403Ser (c.1207C>T)?

AlphaMissense predicts likely benign (score 0.0686) — an in-silico prediction, not a clinical call.

MLH1 p.Pro403Ser

c.1207C>T · rs587778897 · VCV89677

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0686 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Lynch syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0686	likely benign
REVEL	0.547	indeterminate
SaProt	LLR -6.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -3.8
Regional constraint	o/e 0.95	unconstrained · MANE · 57 kb · p 0.11 · regional, not allelic
Overall
CADD	9.637	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 0.000254% European (non-Finnish) · 3/1,179,960 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,704 alleles · very rare exomes 1/1,461,882 · genomes 2/151,822 · 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.Pro403Ser
Coding: c.1207C>T
MANE Select: NM_000249
dbSNP: rs587778897
Type: single nucleotide variant
Location: chr3:37025805 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 403: a UniProt-annotated variant site (no decrease in mismatch repair activity; no effect on nuclear localization); the 'disordered' region

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

Disease context

Lynch syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Muir-Torre syndrome hereditary neoplastic syndrome

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MLH1 p.Pro403Arg Uncertain significance ★★ ⚠ same residue
MLH1 p.Pro403Thr Uncertain significance ★★ ⚠ same residue
MLH1 p.Pro403His Uncertain significance ★ ⚠ same residue
MLH1 p.Pro403fs Pathogenic/Likely pathogenic ★★ same residue
MLH1 p.Pro403= Likely benign ★ same residue
MLH1 c.1038+1G>C Likely pathogenic ★★★ same condition
MLH1 c.1039-1G>A Pathogenic ★★★ same condition
MLH1 c.1039-2A>G 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-pro403ser (accessed [today's date]).

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