Is MLH1 p.Val482= (c.1446G>A) pathogenic?

MLH1 p.Val482= (c.1446G>A) is classified Benign/Likely benign in MLH1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-18). Very rare (popmax 0.00446%, eas); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is MLH1 p.Val482= (c.1446G>A) in the general population?

MLH1 p.Val482= (c.1446G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

MLH1 p.Val482=

Q: What condition is associated with MLH1 p.Val482= (c.1446G>A)?

MLH1 p.Val482= (c.1446G>A) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, Lynch syndrome 2 (ClinVar).

c.1446G>A · rs1417379962 · VCV455389

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.3, phastCons 1
Overall
CADD	10.08	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,890 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000248% 4/1,614,188 alleles · very rare exomes 4/1,461,870 · genomes 0/152,318 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,445
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	8.47e-05%	1,180,022

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.Val482=
Coding: c.1446G>A
MANE Select: NM_000249
dbSNP: rs1417379962
Type: single nucleotide variant
Location: chr3:37028820 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 482: 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

Also linked: Lynch syndrome Lynch syndrome 2 hereditary neoplastic syndrome

Similar variants

MLH1 p.Val482Ala Uncertain significance ★★ ⚠ same residue
MLH1 p.Val482Met Uncertain significance ★★ ⚠ same residue
MLH1 p.Val482Leu Uncertain significance ★ ⚠ same residue
MLH1 p.Val482fs Pathogenic ★ same residue
MLH1 p.Val482_Met490del Uncertain significance ★ same residue
MLH1 p.Val482del Uncertain significance ★ same residue
MLH1 c.1038+1G>C Likely pathogenic ★★★ same condition
MLH1 c.1039-1G>A 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-val482 (accessed [today's date]).

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