Is MLH1 p.Ser486Phe (c.1457C>T) pathogenic?

MLH1 p.Ser486Phe (c.1457C>T) is classified Conflicting classifications of pathogenicity in MLH1 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.1045); Very rare (popmax 0.00668%, eas); Associated with Lynch syndrome.

What condition is associated with MLH1 p.Ser486Phe (c.1457C>T)?

MLH1 p.Ser486Phe (c.1457C>T) is associated with Lynch syndrome, Muir-Torre syndrome, ovarian cancer (ClinVar).

How common is MLH1 p.Ser486Phe (c.1457C>T) in the general population?

MLH1 p.Ser486Phe (c.1457C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

How is Lynch syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MLH1 p.Ser486Phe (c.1457C>T)?

AlphaMissense predicts likely benign (score 0.1045) — an in-silico prediction, not a clinical call.

MLH1 p.Ser486Phe

c.1457C>T · rs532873141 · VCV405411

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1045 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Lynch syndrome

Computational evidence

Protein change
AlphaMissense	0.1045	likely benign
REVEL	0.533	indeterminate
SaProt	LLR -8.34	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP 0.61, phastCons 0.89
Regional constraint	o/e 0.95	unconstrained · MANE · 57 kb · p 0.11 · regional, not allelic
Overall
CADD	20.6	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 0.00668% East Asian · 3/44,892 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000248% 4/1,614,140 alleles · very rare exomes 2/1,461,862 · genomes 2/152,278 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,964
South Asian	0.0011%	91,078

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.Ser486Phe
Coding: c.1457C>T
MANE Select: NM_000249
dbSNP: rs532873141
Type: single nucleotide variant
Location: chr3:37028831 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 486: the 'disordered' region; the 'interaction with exo1' region

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

Disease context

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

Also linked: Muir-Torre syndrome ovarian cancer Lynch syndrome 2 hereditary neoplastic syndrome

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MLH1 p.Ser486= Likely benign ★ same residue
MLH1 p.Ser486fs 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
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

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-ser486phe (accessed [today's date]).

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