Is MLH1 p.Phe99= (c.297T>C) pathogenic?

MLH1 p.Phe99= (c.297T>C) is classified Likely benign in MLH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-06). Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MLH1 p.Phe99= (c.297T>C)?

MLH1 p.Phe99= (c.297T>C) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

How common is MLH1 p.Phe99= (c.297T>C) in the general population?

MLH1 p.Phe99= (c.297T>C) is absent from gnomAD v4.1 (gnomAD).

MLH1 p.Phe99=

c.297T>C · rs267607730 · VCV2833328

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 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.
REVEL	0.556	indeterminate
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.85	GERP -2, phastCons 1
Overall
CADD	9.593	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.Phe99=
Coding: c.297T>C
MANE Select: NM_000249
dbSNP: rs267607730
Type: single nucleotide variant
Location: chr3:37001044 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB

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: hereditary neoplastic syndrome

Similar variants

MLH1 p.Phe99Ser Likely pathogenic ★ same residue
MLH1 p.Phe99Cys Uncertain significance ★ ⚠ same residue
MLH1 p.Phe99_Arg100= Likely benign ★ 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
MLH1 c.117-1G>T 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-phe99 (accessed [today's date]).

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