Is MLH1 p.Ser2= (c.6G>C) pathogenic?

MLH1 p.Ser2= (c.6G>C) is classified Benign/Likely benign in MLH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-15). Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with MLH1 p.Ser2= (c.6G>C)?

MLH1 p.Ser2= (c.6G>C) is associated with hereditary neoplastic syndrome, Lynch syndrome 2 (ClinVar).

How common is MLH1 p.Ser2= (c.6G>C) in the general population?

MLH1 p.Ser2= (c.6G>C) is very rare (popmax 0.00223%, eas) (gnomAD).

MLH1 p.Ser2=

c.6G>C · rs757950578 · VCV1756619

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	phastCons 0.96
Overall
CADD	12.24	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,888 alleles

Overall 6.19e-05% 1/1,614,228 alleles · very rare exomes 1/1,461,868 · genomes 0/152,360 · 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.Ser2=
Coding: c.6G>C
MANE Select: NM_000249
dbSNP: rs757950578
Type: single nucleotide variant
Location: chr3:36993553 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 2: a modified residue (n-acetylserine)

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome 2

Similar variants

MLH1 p.Ser2Ter Pathogenic ★★★ same residue
MLH1 p.Ser2Ala Uncertain significance ★★ ⚠ same residue
MLH1 p.Ser2Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MLH1 p.Ser2del Uncertain significance ★★ same residue
MLH1 p.Ser2Trp Uncertain significance ★ 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-ser2 (accessed [today's date]).

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