Is MLH1 p.Arg423Ser (c.1269G>T) pathogenic?

MLH1 p.Arg423Ser (c.1269G>T) is classified Uncertain significance in MLH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-14). AlphaMissense: likely benign (0.0878); Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MLH1 p.Arg423Ser (c.1269G>T)?

MLH1 p.Arg423Ser (c.1269G>T) is associated with Hereditary nonpolyposis colorectal neoplasms (ClinVar).

How common is MLH1 p.Arg423Ser (c.1269G>T) in the general population?

MLH1 p.Arg423Ser (c.1269G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MLH1 p.Arg423Ser (c.1269G>T)?

AlphaMissense predicts likely benign (score 0.0878) — an in-silico prediction, not a clinical call.

MLH1 p.Arg423Ser

c.1269G>T · rs373076967 · VCV2714895

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0878 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.0878	likely benign
REVEL	0.584	indeterminate
SaProt	LLR -4.08	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.79	GERP -0.66
Regional constraint	o/e 0.95	unconstrained · MANE · 57 kb · p 0.11 · regional, not allelic
Overall
CADD	0.465	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.Arg423Ser
Coding: c.1269G>T
MANE Select: NM_000249
dbSNP: rs373076967
Type: single nucleotide variant
Location: chr3:37025867 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 423: a UniProt-annotated variant site (no effect on protein expression); the 'disordered' region; the 'interaction with exo1' region

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.Arg423= Conflicting classifications of pathogenicity ★ same residue
MLH1 p.Arg423Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
MLH1 p.Arg423Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
MLH1 p.Arg423Gly Likely 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-arg423ser (accessed [today's date]).

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