Is MLH1 p.Ser337Phe (c.1010C>T) pathogenic?

MLH1 p.Ser337Phe (c.1010C>T) is classified Uncertain significance in MLH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-27). AlphaMissense: ambiguous (0.4084); Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MLH1 p.Ser337Phe (c.1010C>T)?

MLH1 p.Ser337Phe (c.1010C>T) is associated with Hereditary nonpolyposis colorectal neoplasms (ClinVar).

How common is MLH1 p.Ser337Phe (c.1010C>T) in the general population?

MLH1 p.Ser337Phe (c.1010C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MLH1 p.Ser337Phe (c.1010C>T)?

AlphaMissense predicts ambiguous (score 0.4084) — an in-silico prediction, not a clinical call.

MLH1 p.Ser337Phe

c.1010C>T · VCV4801630

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4084 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.4084	ambiguous
REVEL	0.768	pathogenic-leaning
SaProt	LLR -12.50	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 57 kb · p 0.11 · regional, not allelic
Overall
CADD	27.0	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.Ser337Phe
Coding: c.1010C>T
MANE Select: NM_000249
Type: single nucleotide variant
Location: chr3:37020435 (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

Similar variants

MLH1 p.Ser337Cys Uncertain significance ★★ ⚠ same residue
MLH1 p.Ser337Pro Uncertain significance ★ ⚠ same residue
MLH1 p.Ser337Tyr Uncertain significance ★ ⚠ same residue
MLH1 p.Ser337= Benign ★ same residue
MLH1 c.1039-1G>C Pathogenic/Likely pathogenic ★★ same condition
MLH1 c.1039-2A>C Pathogenic/Likely pathogenic ★★ same condition
MLH1 c.116+1G>C Pathogenic/Likely pathogenic ★★ same condition
MLH1 c.116+1G>T Pathogenic/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-ser337phe (accessed [today's date]).

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