Is MLH3 p.Arg93= (c.279A>G) pathogenic?

MLH3 p.Arg93= (c.279A>G) is classified Likely benign in MLH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-30). Very rare (popmax 8.47e-05%, nfe).

How common is MLH3 p.Arg93= (c.279A>G) in the general population?

MLH3 p.Arg93= (c.279A>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

MLH3 p.Arg93=

c.279A>G · VCV4552109

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

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
Constraint at this position
Conservation	phyloP -0.19	GERP -2.5, phastCons 0.66
Overall
CADD	6.268	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,028 alleles

Overall 6.2e-05% 1/1,614,028 alleles · very rare exomes 1/1,461,720 · genomes 0/152,308 · 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: MLH3
Protein: p.Arg93=
Coding: c.279A>G
MANE Select: NM_001040108
Type: single nucleotide variant
Location: chr14:75049377 (GRCh38)
Gene constraint: LOEUF 0.735 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 56.14
Residue 93: a UniProt-annotated variant site (in)

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

Similar variants

MLH3 p.Arg93Gln Uncertain significance ★★ ⚠ same residue
MLH3 p.Arg93Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
MLH3 p.Arg93Pro Uncertain significance ★ ⚠ same residue
MLH3 p.Arg93Ter Conflicting classifications of pathogenicity ★ same residue
MLH3 p.Gln1360Ter Pathogenic ★★ same type
MLH3 p.Gln423Ter Pathogenic ★★ same type
MLH3 p.Ser626Ter Pathogenic ★★ same type
MLH3 p.Tyr441Ter Pathogenic ★★ same type

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-arg93 (accessed [today's date]).

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