Is MLH1 p.Ser87Phe (c.260C>T) pathogenic?

MLH1 p.Ser87Phe (c.260C>T) is classified Uncertain significance in MLH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-10). AlphaMissense: likely benign (0.2119); Very rare (popmax 0.0011%, sas); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MLH1 p.Ser87Phe (c.260C>T)?

MLH1 p.Ser87Phe (c.260C>T) is associated with Hereditary nonpolyposis colorectal neoplasms (ClinVar).

How common is MLH1 p.Ser87Phe (c.260C>T) in the general population?

MLH1 p.Ser87Phe (c.260C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about MLH1 p.Ser87Phe (c.260C>T)?

AlphaMissense predicts likely benign (score 0.2119) — an in-silico prediction, not a clinical call.

MLH1 p.Ser87Phe

c.260C>T · rs2081469787 · VCV1904297

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2119 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.2119	likely benign
REVEL	0.664	pathogenic-leaning
SaProt	LLR -11.15	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.1	phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 57 kb · p 0.11 · regional, not allelic
Overall
CADD	25.1	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

Grpmax group 0.0011% South Asian · 1/91,038 alleles

Overall 6.2e-05% 1/1,612,484 alleles · very rare exomes 1/1,460,352 · genomes 0/152,132 · 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.Ser87Phe
Coding: c.260C>T
MANE Select: NM_000249
dbSNP: rs2081469787
Type: single nucleotide variant
Location: chr3:37001007 (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.Ser87Cys Uncertain significance ★★ ⚠ same residue
MLH1 p.Ser87= Benign/Likely benign ★★ same residue
MLH1 p.Ser87Ala Uncertain significance ★ ⚠ same residue
MLH1 p.Ser87Pro Uncertain significance ★ ⚠ 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-ser87phe (accessed [today's date]).

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