Is MLH1 p.Pro28Ser (c.82C>T) pathogenic?

MLH1 p.Pro28Ser (c.82C>T) is classified Conflicting classifications of pathogenicity in MLH1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-02). AlphaMissense: likely pathogenic (0.971); Very rare (popmax 0.00133%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with MLH1 p.Pro28Ser (c.82C>T)?

MLH1 p.Pro28Ser (c.82C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MLH1 p.Pro28Ser (c.82C>T) in the general population?

MLH1 p.Pro28Ser (c.82C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about MLH1 p.Pro28Ser (c.82C>T)?

AlphaMissense predicts likely pathogenic (score 0.971) — an in-silico prediction, not a clinical call.

MLH1 p.Pro28Ser

c.82C>T · rs1559500757 · VCV627728

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.971 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.971	likely pathogenic
REVEL	0.878	moderately pathogenic-leaning
SaProt	LLR -14.97	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 57 kb · p 0.11 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,052 alleles

Overall 6.2e-05% 1/1,614,184 alleles · very rare exomes 1/1,461,870 · genomes 0/152,314 · 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.Pro28Ser
Coding: c.82C>T
MANE Select: NM_000249
dbSNP: rs1559500757
Type: single nucleotide variant
Location: chr3:36993629 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 28: an α-helix; a UniProt-annotated variant site (in lynch2; loss of protein expression; normal interaction with pms2 and exo1; decreased mismatch repair activity; no effect on nuclear localization)

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

Similar variants

MLH1 p.Pro28Leu Pathogenic ★★★ same residue
MLH1 p.Pro28Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
MLH1 p.Pro28= Likely benign ★ same residue
MLH1 p.Pro28Arg Likely pathogenic ★ same residue
MLH1 c.1039-1G>A Pathogenic ★★★ same condition
MLH1 c.1039-2A>T Likely pathogenic ★★★ same condition
MLH1 c.116+1G>A Likely pathogenic ★★★ same condition
MLH1 c.116+5G>C 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-pro28ser (accessed [today's date]).

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