Is MLH3 p.Asp136= (c.408T>C) pathogenic?

MLH3 p.Asp136= (c.408T>C) is classified Benign/Likely benign in MLH3 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-04-28). Rare (popmax 0.869%, nfe); Associated with colorectal cancer.

What condition is associated with MLH3 p.Asp136= (c.408T>C)?

MLH3 p.Asp136= (c.408T>C) is associated with colorectal cancer, endometrial carcinoma, colorectal cancer, hereditary nonpolyposis, type 7 (ClinVar).

How common is MLH3 p.Asp136= (c.408T>C) in the general population?

MLH3 p.Asp136= (c.408T>C) is rare (popmax 0.869%, nfe) (gnomAD).

MLH3 p.Asp136=

c.408T>C · rs61755655 · VCV221150

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.869%, nfe)

Conditions

colorectal cancer

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 0.31	GERP -3.2, phastCons 0.016
Overall
CADD	1.963	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.869% European (non-Finnish) · 10,253/1,180,040 alleles

Filtering AF 0.855% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.849%

Overall 0.701% 11,320/1,614,242 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.869%	115
Admixed American	0.578%	173
Remaining individualsnot grpmax-eligible	0.566%	177
Middle Eastern	0.412%	242
Ashkenazi Jewishnot grpmax-eligible	0.331%	302
Finnishnot grpmax-eligible	0.197%	508
African / African-American	0.129%	774
South Asian	0.022%	4,554

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: MLH3
Protein: p.Asp136=
Coding: c.408T>C
MANE Select: NM_001040108
dbSNP: rs61755655
Type: single nucleotide variant
Location: chr14:75049248 (GRCh38)
Gene constraint: LOEUF 0.735 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 56.14

Full MLH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

colorectal cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: endometrial carcinoma colorectal cancer, hereditary nonpolyposis, type 7

Similar variants

MLH3 p.Asp136fs Conflicting classifications of pathogenicity ★ same residue
MLH3 p.Asp136Asn Uncertain significance ★ ⚠ same residue
MLH3 p.Asp136His Uncertain significance ★ ⚠ same residue
MLH3 p.Gln1360Ter Pathogenic ★★ same condition
MLH3 p.Gln423Ter Pathogenic ★★ same condition
MLH3 p.Ser626Ter Pathogenic ★★ same condition
MLH3 p.Tyr441Ter Pathogenic ★★ same condition
MLH3 c.3280+4A>G Uncertain significance ★★ 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/mlh3-p-asp136 (accessed [today's date]).

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