Is MLH1 p.Ile150= (c.450C>T) pathogenic?

MLH1 p.Ile150= (c.450C>T) is classified Benign/Likely benign in MLH1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-19). Very rare (popmax 0.00267%, afr); Associated with mismatch repair cancer syndrome 1.

What condition is associated with MLH1 p.Ile150= (c.450C>T)?

MLH1 p.Ile150= (c.450C>T) is associated with mismatch repair cancer syndrome 1, Lynch syndrome 2, hereditary neoplastic syndrome (ClinVar).

How common is MLH1 p.Ile150= (c.450C>T) in the general population?

MLH1 p.Ile150= (c.450C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

MLH1 p.Ile150=

Q: How is Constitutional mismatch repair deficiency syndrome inherited?

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

c.450C>T · rs950640785 · VCV3230783

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

mismatch repair cancer syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.074	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.41	GERP -3, phastCons 0.99
Overall
CADD	8.881	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,880 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,612,374 alleles · very rare exomes 0/1,460,252 · genomes 2/152,122 · 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.Ile150=
Coding: c.450C>T
MANE Select: NM_000249
dbSNP: rs950640785
Type: single nucleotide variant
Location: chr3:37007060 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 150: a β-strand

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

Disease context

mismatch repair cancer syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome 2 hereditary neoplastic syndrome

For Constitutional mismatch repair deficiency syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

MLH1 p.Ile150Asn Uncertain significance ★★ ⚠ same residue
MLH1 p.Ile150Leu Uncertain significance ★★ ⚠ same residue
MLH1 p.Ile150Met Uncertain significance ★ ⚠ 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
MLH1 c.1039-2A>T Likely pathogenic ★★★ same condition
MLH1 c.116+1G>A 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-ile150 (accessed [today's date]).

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