Is MLH1 p.Ser339= (c.1017C>T) pathogenic?

MLH1 p.Ser339= (c.1017C>T) is classified Likely benign in MLH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-02). Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is MLH1 p.Ser339= (c.1017C>T) in the general population?

MLH1 p.Ser339= (c.1017C>T) is absent from gnomAD v4.1 (gnomAD).

MLH1 p.Ser339=

Q: What condition is associated with MLH1 p.Ser339= (c.1017C>T)?

MLH1 p.Ser339= (c.1017C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

c.1017C>T · rs2125854598 · VCV3018829

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	0.049	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -4.4
Overall
CADD	7.344	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.Ser339=
Coding: c.1017C>T
MANE Select: NM_000249
dbSNP: rs2125854598
Type: single nucleotide variant
Location: chr3:37020442 (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.Ser339Ala Uncertain significance ★ ⚠ same residue
MLH1 p.Ser339fs Pathogenic ★★ same residue
MLH1 p.Ser339Phe Uncertain significance ★ ⚠ 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-ser339 (accessed [today's date]).

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