Is MLH1 p.Gln537Ter (c.1609C>T) pathogenic?

MLH1 p.Gln537Ter (c.1609C>T) is classified Pathogenic in MLH1 (ClinVar, Expert panel, 5 submitters; last evaluated 2013-09-05). Absent from gnomAD v4.1; Associated with Lynch syndrome.

What condition is associated with MLH1 p.Gln537Ter (c.1609C>T)?

MLH1 p.Gln537Ter (c.1609C>T) is associated with Lynch syndrome, Lynch syndrome 2, hereditary neoplastic syndrome (ClinVar).

How common is MLH1 p.Gln537Ter (c.1609C>T) in the general population?

MLH1 p.Gln537Ter (c.1609C>T) is absent from gnomAD v4.1 (gnomAD).

How is Lynch syndrome inherited?

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

MLH1 p.Gln537Ter

c.1609C>T · rs63751277 · VCV89801

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Lynch syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 14 of 19
Splicing
SpliceAI	Δ0.20	acceptor loss, 50 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Overall
CADD	41.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MLH1
Protein: p.Gln537Ter
Coding: c.1609C>T
MANE Select: NM_000249
dbSNP: rs63751277
Type: single nucleotide variant
Location: chr3:37040236 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 537: a β-strand; the 'interaction with exo1' region

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

Disease context

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

Also linked: Lynch syndrome 2 hereditary neoplastic syndrome

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MLH1 p.Gln537Leu Uncertain significance ★★ ⚠ same residue
MLH1 p.Gln537= Benign/Likely benign ★★ same residue
MLH1 p.Gln537His Uncertain significance ★ ⚠ same residue
MLH1 p.Gln537fs Pathogenic ★★ same residue
MLH1 p.Gln537delinsValTer Pathogenic ★ same residue
MLH1 p.Gln537Pro Uncertain significance ★ ⚠ same residue
MLH1 c.1038+1G>C Likely pathogenic ★★★ same condition
MLH1 c.1039-1G>A 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-gln537ter (accessed [today's date]).

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