Is MLH1 p.Arg385Pro (c.1154G>C) pathogenic?

MLH1 p.Arg385Pro (c.1154G>C) is classified Conflicting classifications of pathogenicity in MLH1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-05-05). AlphaMissense: likely pathogenic (0.9955); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with MLH1 p.Arg385Pro (c.1154G>C)?

MLH1 p.Arg385Pro (c.1154G>C) is associated with hereditary neoplastic syndrome, Lynch syndrome 2 (ClinVar).

How common is MLH1 p.Arg385Pro (c.1154G>C) in the general population?

MLH1 p.Arg385Pro (c.1154G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MLH1 p.Arg385Pro (c.1154G>C)?

AlphaMissense predicts likely pathogenic (score 0.9955) — an in-silico prediction, not a clinical call.

MLH1 p.Arg385Pro

c.1154G>C · rs63750430 · VCV89654

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9955 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9955	likely pathogenic · top 5% in MLH1
REVEL	0.929	moderately pathogenic-leaning
SaProt	LLR -9.01	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 57 kb · p 0.11 · regional, not allelic
Overall
CADD	29.1	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

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.Arg385Pro
Coding: c.1154G>C
MANE Select: NM_000249
dbSNP: rs63750430
Type: single nucleotide variant
Location: chr3:37025752 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 385: a UniProt-annotated variant site (in lynch2; uncertain significance)

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

Also linked: Lynch syndrome 2

Similar variants

MLH1 p.Arg385Leu Uncertain significance ★★ ⚠ same residue
MLH1 p.Arg385Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
MLH1 p.Arg385Gly Uncertain significance ★ ⚠ same residue
MLH1 p.Arg385His Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg385pro (accessed [today's date]).

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