Is MLH1 p.Pro435Ser (c.1303C>T) pathogenic?

MLH1 p.Pro435Ser (c.1303C>T) is classified Uncertain significance in MLH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-07-24). AlphaMissense: likely benign (0.0739); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with MLH1 p.Pro435Ser (c.1303C>T)?

MLH1 p.Pro435Ser (c.1303C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MLH1 p.Pro435Ser (c.1303C>T) in the general population?

MLH1 p.Pro435Ser (c.1303C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MLH1 p.Pro435Ser (c.1303C>T)?

AlphaMissense predicts likely benign (score 0.0739) — an in-silico prediction, not a clinical call.

MLH1 p.Pro435Ser

c.1303C>T · rs786202922 · VCV1769460

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0739 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0739	likely benign
REVEL	0.489	indeterminate
SaProt	LLR -5.56	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
Regional constraint	o/e 0.95	unconstrained · MANE · 57 kb · p 0.11 · regional, not allelic
Overall
CADD	18.04	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.Pro435Ser
Coding: c.1303C>T
MANE Select: NM_000249
dbSNP: rs786202922
Type: single nucleotide variant
Location: chr3:37025901 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 435: 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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MLH1 p.Pro435Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
MLH1 p.Pro435fs 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
MLH1 c.117-2A>G 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-pro435ser (accessed [today's date]).

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