Is MLH1 p.Arg69= (c.205A>C) pathogenic?

MLH1 p.Arg69= (c.205A>C) is classified Uncertain significance in MLH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-07). Very rare (popmax 0.0011%, sas); Associated with Lynch syndrome 2.

What condition is associated with MLH1 p.Arg69= (c.205A>C)?

MLH1 p.Arg69= (c.205A>C) is associated with Lynch syndrome 2 (ClinVar).

How common is MLH1 p.Arg69= (c.205A>C) in the general population?

MLH1 p.Arg69= (c.205A>C) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Lynch syndrome inherited?

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

MLH1 p.Arg69=

c.205A>C · VCV4056178

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Lynch syndrome 2

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 3	phastCons 1
Overall
CADD	13.09	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,010 alleles

Overall 6.21e-05% 1/1,610,642 alleles · very rare exomes 1/1,458,280 · genomes 0/152,362 · 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.Arg69=
Coding: c.205A>C
MANE Select: NM_000249
Type: single nucleotide variant
Location: chr3:36996707 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 69: a UniProt-annotated variant site (in lynch2; decreased mismatch repair activity)

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

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MLH1 p.Arg69Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
MLH1 p.Arg69Thr Uncertain significance ★★ ⚠ same residue
MLH1 p.Arg69Gly Uncertain significance ★ ⚠ same residue
MLH1 p.Arg69Met 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.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-arg69 (accessed [today's date]).

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