Is MLH1 p.Arg265Pro (c.794G>C) pathogenic?

MLH1 p.Arg265Pro (c.794G>C) is classified Likely pathogenic in MLH1 (ClinVar, Expert panel, 6 submitters; last evaluated 2018-06-13). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1; Associated with Lynch syndrome 1.

What condition is associated with MLH1 p.Arg265Pro (c.794G>C)?

MLH1 p.Arg265Pro (c.794G>C) is associated with Lynch syndrome 1, Lynch syndrome 2, hereditary neoplastic syndrome (ClinVar).

How common is MLH1 p.Arg265Pro (c.794G>C) in the general population?

MLH1 p.Arg265Pro (c.794G>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.Arg265Pro (c.794G>C)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

MLH1 p.Arg265Pro

c.794G>C · rs63751448 · VCV433856

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Lynch syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic ✓ concordant with ClinVar · top 1% in MLH1
REVEL	0.979	strongly pathogenic-leaning
SaProt	LLR -13.34	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.20	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 57 kb · p 0.11 · regional, not allelic
Overall
CADD	33.0	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

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.Arg265Pro
Coding: c.794G>C
MANE Select: NM_000249
dbSNP: rs63751448
Type: single nucleotide variant
Location: chr3:37017509 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 265: a UniProt-annotated variant site (in lynch2); a UniProt-annotated variant site (in lynch2; results in partial mlh1 exon 10 skipping on ex vivo splicing assay; decreased mismatch repair activity; no effect on nuclear localization); a UniProt-annotated variant site (risk factor for lynch2; results in partial mlh1 exon 10 skipping on ex vivo splicing assay; decreased mismatch repair activity); a UniProt-annotated variant site (in lynch2; decreased mismatch repair activity)

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

Disease context

Lynch syndrome 1 — 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.Arg265Cys Pathogenic ★★★ same residue
MLH1 p.Arg265Ser Pathogenic ★★★ same residue
MLH1 p.Arg265Gly Pathogenic/Likely pathogenic ★★ same residue
MLH1 p.Arg265Leu Uncertain significance ★★ ⚠ same residue
MLH1 p.Arg265= Likely benign ★★ same residue
MLH1 p.Arg265His Conflicting classifications of pathogenicity ★ ⚠ same residue
MLH1 p.Arg265fs Pathogenic/Likely pathogenic ★★ same residue
MLH1 c.1038+1G>C 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-arg265pro (accessed [today's date]).

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