Is MLH1 p.Val152= (c.456G>A) pathogenic?

MLH1 p.Val152= (c.456G>A) is classified Likely benign in MLH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-17). Very rare (popmax 0.00133%, afr); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MLH1 p.Val152= (c.456G>A)?

MLH1 p.Val152= (c.456G>A) is associated with Hereditary nonpolyposis colorectal neoplasms (ClinVar).

How common is MLH1 p.Val152= (c.456G>A) in the general population?

MLH1 p.Val152= (c.456G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

MLH1 p.Val152=

c.456G>A · rs2125783411 · VCV1137048

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Pangolin	Δ0.30	loss · gain 0.09 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 1.6	GERP -0.17, phastCons 1
Overall
CADD	15.49	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,980 alleles

Overall 6.2e-05% 1/1,612,574 alleles · very rare exomes 1/1,460,312 · genomes 0/152,262 · 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.Val152=
Coding: c.456G>A
MANE Select: NM_000249
dbSNP: rs2125783411
Type: single nucleotide variant
Location: chr3:37008816 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 152: a β-strand

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.Val152Leu Uncertain significance ★★ ⚠ same residue
MLH1 p.Val152Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
MLH1 p.Val152Met Conflicting classifications of pathogenicity ★ ⚠ same residue
MLH1 p.Val152Glu Uncertain significance ★ ⚠ 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-val152 (accessed [today's date]).

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