Is MLH1 p.Arg100Pro (c.299G>C) pathogenic?

MLH1 p.Arg100Pro (c.299G>C) is classified Pathogenic in MLH1 (ClinVar, Expert panel, 7 submitters; last evaluated 2018-03-09). AlphaMissense: likely pathogenic (0.9994); Absent from gnomAD v4.1; Associated with Lynch syndrome 1.

What condition is associated with MLH1 p.Arg100Pro (c.299G>C)?

MLH1 p.Arg100Pro (c.299G>C) is associated with Lynch syndrome 1, Lynch syndrome 2, hereditary nonpolyposis colon cancer (ClinVar).

How common is MLH1 p.Arg100Pro (c.299G>C) in the general population?

MLH1 p.Arg100Pro (c.299G>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.Arg100Pro (c.299G>C)?

AlphaMissense predicts likely pathogenic (score 0.9994) — an in-silico prediction, not a clinical call.

MLH1 p.Arg100Pro

c.299G>C · rs63750266 · VCV90133

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9994 · 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	0.9994	likely pathogenic ✓ concordant with ClinVar · top 1% in MLH1
REVEL	0.885	moderately pathogenic-leaning
SaProt	LLR -11.79	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.40 · evaluated, not missing
Pangolin	Δ0.30	gain · loss 0.10 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.8, 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.Arg100Pro
Coding: c.299G>C
MANE Select: NM_000249
dbSNP: rs63750266
Type: single nucleotide variant
Location: chr3:37001046 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 100: a binding site

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 nonpolyposis colon cancer

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MLH1 p.Arg100Ter Pathogenic ★★★ same residue
MLH1 p.Arg100Gln Uncertain significance ★★ ⚠ same residue
MLH1 p.Arg100Leu Uncertain significance ★★ ⚠ same residue
MLH1 p.Arg100Gly Uncertain significance ★ ⚠ same residue
MLH1 p.Arg100= Likely benign ★ 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

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-arg100pro (accessed [today's date]).

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