Is MLH1 p.Phe683= (c.2049C>T) pathogenic?

MLH1 p.Phe683= (c.2049C>T) is classified Benign/Likely benign in MLH1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-24). Very rare (popmax 0.0011%, sas); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MLH1 p.Phe683= (c.2049C>T)?

MLH1 p.Phe683= (c.2049C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 2, hereditary neoplastic syndrome (ClinVar).

How common is MLH1 p.Phe683= (c.2049C>T) in the general population?

MLH1 p.Phe683= (c.2049C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

MLH1 p.Phe683=

c.2049C>T · rs1449199195 · VCV2773586

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

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 -0.17	GERP -3.7, phastCons 0.66
Overall
CADD	5.943	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,074 alleles

Overall 6.2e-05% 1/1,614,112 alleles · very rare exomes 1/1,461,826 · genomes 0/152,286 · 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.Phe683=
Coding: c.2049C>T
MANE Select: NM_000249
dbSNP: rs1449199195
Type: single nucleotide variant
Location: chr3:37048963 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 683: an α-helix

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.Phe683Ser Likely pathogenic ★★★ same residue
MLH1 p.Phe683Val Likely pathogenic ★ same residue
MLH1 p.Phe683Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MLH1 p.Phe683del Likely pathogenic ★ same residue
MLH1 p.Phe683fs Pathogenic ★ 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-phe683 (accessed [today's date]).

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