Is MLH1 p.Pro648= (c.1944C>T) pathogenic?

MLH1 p.Pro648= (c.1944C>T) is classified Benign/Likely benign in MLH1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-28). Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MLH1 p.Pro648= (c.1944C>T)?

MLH1 p.Pro648= (c.1944C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 2, hereditary neoplastic syndrome (ClinVar).

How common is MLH1 p.Pro648= (c.1944C>T) in the general population?

MLH1 p.Pro648= (c.1944C>T) is absent from gnomAD v4.1 (gnomAD).

MLH1 p.Pro648=

c.1944C>T · rs1553663936 · VCV1137433

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.67	GERP 0.58, phastCons 0.007
Overall
CADD	6.501	PHRED · no single calibrated threshold — expert panels disagree

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.Pro648=
Coding: c.1944C>T
MANE Select: NM_000249
dbSNP: rs1553663936
Type: single nucleotide variant
Location: chr3:37048564 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 648: a UniProt-annotated variant site (in lynch2; decreased mismatch repair activity; defective in interaction with pms2; loss of protein expression; loss of nuclear localization); a UniProt-annotated variant site (in lynch2; defective in interaction with pms2 and exo1; may lose nuclear localization; loss of protein expression; no decrease in mismatch repair activity); a UniProt-annotated variant site (in lynch2; the protein is unstable; loss of nuclear localization; loss of protein expression; no decrease in mismatch repair activity); the 'interaction with exo1' region

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

Disease context

Hereditary nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome 2 hereditary neoplastic syndrome

Similar variants

MLH1 p.Pro648Leu Likely pathogenic ★★★ same residue
MLH1 p.Pro648Ser Pathogenic ★★★ same residue
MLH1 p.Pro648Arg Likely pathogenic ★★ same residue
MLH1 p.Pro648His Likely pathogenic ★ same residue
MLH1 p.Pro648Thr Likely pathogenic ★ same residue
MLH1 p.Pro648Ala Conflicting classifications of pathogenicity ★ ⚠ 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-pro648 (accessed [today's date]).

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