Is MLH1 p.Pro350= (c.1050A>G) pathogenic?

MLH1 p.Pro350= (c.1050A>G) is classified Benign/Likely benign in MLH1 (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-02-04). Ultra-rare (popmax 0.0855%, amr); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MLH1 p.Pro350= (c.1050A>G)?

MLH1 p.Pro350= (c.1050A>G) is associated with Hereditary nonpolyposis colorectal neoplasms, Muir-Torre syndrome, Lynch syndrome 2 (ClinVar).

How common is MLH1 p.Pro350= (c.1050A>G) in the general population?

MLH1 p.Pro350= (c.1050A>G) is ultra-rare (popmax 0.0855%, amr) (gnomAD).

MLH1 p.Pro350=

c.1050A>G · rs137937003 · VCV135844

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0855%, amr)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.021	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.038	GERP -5.3, phastCons 0.007
Overall
CADD	9.308	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0855% Admixed American · 42/49,096 alleles

Filtering AF 0.065% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0578%

Overall 0.00654% 95/1,452,710 alleles · ultra-rare exomes 79/1,314,844 · genomes 16/137,866 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0855%	1,169
Remaining individualsnot grpmax-eligible	0.0254%	3,931
European (non-Finnish)	0.00329%	30,435
African / African-American	0.0031%	32,256
South Asian	0.00161%	62,008

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.Pro350=
Coding: c.1050A>G
MANE Select: NM_000249
dbSNP: rs137937003
Type: single nucleotide variant
Location: chr3:37025648 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB

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: Muir-Torre syndrome Lynch syndrome 2 hereditary neoplastic syndrome

Similar variants

MLH1 p.Pro350Arg Uncertain significance ★★ ⚠ same residue
MLH1 p.Pro350Ser Uncertain significance ★★ ⚠ same residue
MLH1 p.Pro350Leu Uncertain significance ★ ⚠ same residue
MLH1 p.Pro350fs Pathogenic ★★ same residue
MLH1 c.1038+1G>C Likely pathogenic ★★★ same condition
MLH1 c.1039-1G>A Pathogenic ★★★ same condition
MLH1 c.1039-2A>G Likely pathogenic ★★★ same condition
MLH1 c.1039-2A>T 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-pro350 (accessed [today's date]).

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