Is MLH3 p.Val148= (c.444G>C) pathogenic?

MLH3 p.Val148= (c.444G>C) is classified Benign in MLH3 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-04-28). Common (popmax 6.37%, afr) — too common for a highly-penetrant pathogenic allele; Associated with colorectal cancer.

What condition is associated with MLH3 p.Val148= (c.444G>C)?

MLH3 p.Val148= (c.444G>C) is associated with colorectal cancer, endometrial carcinoma, colorectal cancer, hereditary nonpolyposis, type 7 (ClinVar).

MLH3 p.Val148=

Q: How common is MLH3 p.Val148= (c.444G>C) in the general population?

MLH3 p.Val148= (c.444G>C) is common (popmax 6.37%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.444G>C · rs11556091 · VCV221151

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

gnomAD v4.1

Common

common (popmax 6.37%, afr) — too common for a highly-penetrant pathogenic allele

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 -5.6	GERP -3.2
Overall
CADD	0.064	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.37% African / African-American · 4,781/75,040 alleles

Filtering AF 6.22% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.16%

Overall 0.324% 5,230/1,614,208 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.37%	16
Remaining individualsnot grpmax-eligible	0.338%	296
Admixed American	0.283%	353
Middle Eastern	0.165%	606
South Asian	0.0132%	7,590
European (non-Finnish)	0.0039%	25,653

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.Val148=
Coding: c.444G>C
MANE Select: NM_001040108
dbSNP: rs11556091
Type: single nucleotide variant
Location: chr14:75049212 (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.Val148Ala Uncertain significance ★★ ⚠ same residue
MLH3 p.Val148Gly Uncertain significance ★★ ⚠ same residue
MLH3 p.Val148Leu 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-val148 (accessed [today's date]).

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