Is MLH1 p.Ser271Phe (c.812C>T) pathogenic?

MLH1 p.Ser271Phe (c.812C>T) is classified Uncertain significance in MLH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-12). AlphaMissense: likely benign (0.1664); Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is MLH1 p.Ser271Phe (c.812C>T) in the general population?

MLH1 p.Ser271Phe (c.812C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MLH1 p.Ser271Phe (c.812C>T)?

AlphaMissense predicts likely benign (score 0.1664) — an in-silico prediction, not a clinical call.

MLH1 p.Ser271Phe

Q: What condition is associated with MLH1 p.Ser271Phe (c.812C>T)?

MLH1 p.Ser271Phe (c.812C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

c.812C>T · rs2125837002 · VCV1515545

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1664 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.1664	likely benign
REVEL	0.664	pathogenic-leaning
SaProt	LLR -10.25	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 57 kb · p 0.11 · regional, not allelic
Overall
CADD	26.9	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.Ser271Phe
Coding: c.812C>T
MANE Select: NM_000249
dbSNP: rs2125837002
Type: single nucleotide variant
Location: chr3:37017527 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 271: an α-helix; a UniProt-annotated variant site (in lynch2)

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.Ser271Cys Uncertain significance ★★ ⚠ same residue
MLH1 p.Ser271= Likely benign ★ same residue
MLH1 p.Ser271_Leu272insTer Pathogenic ★★ 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-ser271phe (accessed [today's date]).

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