Is MLH1 p.Ser44Pro (c.130T>C) pathogenic?

MLH1 p.Ser44Pro (c.130T>C) is classified Uncertain significance in MLH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-20). AlphaMissense: likely pathogenic (0.98); Absent from gnomAD v4.1; Associated with Lynch syndrome.

What condition is associated with MLH1 p.Ser44Pro (c.130T>C)?

MLH1 p.Ser44Pro (c.130T>C) is associated with Lynch syndrome (ClinVar).

How common is MLH1 p.Ser44Pro (c.130T>C) in the general population?

MLH1 p.Ser44Pro (c.130T>C) 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.

What do computational predictors say about MLH1 p.Ser44Pro (c.130T>C)?

AlphaMissense predicts likely pathogenic (score 0.98) — an in-silico prediction, not a clinical call.

MLH1 p.Ser44Pro

c.130T>C · rs63750939 · VCV3074546

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.98 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Lynch syndrome

Computational evidence

Protein change
AlphaMissense	0.98	likely pathogenic
REVEL	0.812	moderately pathogenic-leaning
SaProt	LLR -12.81	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 57 kb · p 0.11 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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.Ser44Pro
Coding: c.130T>C
MANE Select: NM_000249
dbSNP: rs63750939
Type: single nucleotide variant
Location: chr3:36996632 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 44: a UniProt-annotated variant site (in lynch2; no effect on mlh1 splicing; loss of mismatch repair activity)

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

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MLH1 p.Ser44Tyr Pathogenic/Likely pathogenic ★★ same residue
MLH1 p.Ser44= Likely benign ★★ same residue
MLH1 p.Ser44Cys 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-ser44pro (accessed [today's date]).

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