Is MLH1 p.Val384= (c.1152T>C) pathogenic?

MLH1 p.Val384= (c.1152T>C) is classified Likely benign in MLH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-14). Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with MLH1 p.Val384= (c.1152T>C)?

MLH1 p.Val384= (c.1152T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MLH1 p.Val384= (c.1152T>C) in the general population?

MLH1 p.Val384= (c.1152T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

MLH1 p.Val384=

c.1152T>C · rs1401590540 · VCV818432

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.019	moderately benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.52 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.1	GERP -4.6, phastCons 0.001
Overall
CADD	5.789	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,870 alleles

Overall 6.2e-05% 1/1,613,828 alleles · very rare exomes 1/1,461,888 · genomes 0/151,940 · joint denominator

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.Val384=
Coding: c.1152T>C
MANE Select: NM_000249
dbSNP: rs1401590540
Type: single nucleotide variant
Location: chr3:37025750 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 384: a UniProt-annotated variant site (probable risk factor for hnpcc in some populations)

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.Val384Asp Benign ★★★ ⚠ same residue
MLH1 p.Val384Phe Uncertain significance ★★ ⚠ same residue
MLH1 p.Val384Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
MLH1 p.Val384Ala Uncertain significance ★ ⚠ 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

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-val384 (accessed [today's date]).

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