Is MLH1 p.Pro581= (c.1743G>A) pathogenic?

MLH1 p.Pro581= (c.1743G>A) is classified Conflicting classifications of pathogenicity in MLH1 (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-01-11). Ultra-rare (popmax 0.0156%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with MLH1 p.Pro581= (c.1743G>A)?

MLH1 p.Pro581= (c.1743G>A) is associated with hereditary neoplastic syndrome, Lynch syndrome, Muir-Torre syndrome (ClinVar).

How common is MLH1 p.Pro581= (c.1743G>A) in the general population?

MLH1 p.Pro581= (c.1743G>A) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

MLH1 p.Pro581=

c.1743G>A · rs567838745 · VCV185937

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.013	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.8	GERP -4.3
Overall
CADD	0.878	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,878 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00254% 41/1,614,078 alleles · ultra-rare exomes 35/1,461,820 · genomes 6/152,258 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,411
Admixed American	0.01%	10,002
African / African-American	0.00933%	10,718
South Asian	0.00549%	18,216
Finnishnot grpmax-eligible	0.00156%	64,018
European (non-Finnish)	0.00127%	78,665

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.Pro581=
Coding: c.1743G>A
MANE Select: NM_000249
dbSNP: rs567838745
Type: single nucleotide variant
Location: chr3:37047530 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 581: a UniProt-annotated variant site (in lynch2; decreased mismatch repair activity; defective in interaction with pms2); a β-strand; the 'interaction with exo1' region

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

Also linked: Lynch syndrome Muir-Torre syndrome Lynch syndrome 2

Similar variants

MLH1 p.Pro581Leu Likely benign ★★★ ⚠ same residue
MLH1 p.Pro581Gln Uncertain significance ★ ⚠ same residue
MLH1 p.Pro581fs Pathogenic/Likely pathogenic ★★ 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-pro581 (accessed [today's date]).

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