Is MLH1 p.Asp74= (c.222T>C) pathogenic?

MLH1 p.Asp74= (c.222T>C) is classified Conflicting classifications of pathogenicity in MLH1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-27). Very rare (popmax 0.00318%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MLH1 p.Asp74= (c.222T>C)?

MLH1 p.Asp74= (c.222T>C) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 2, hereditary neoplastic syndrome (ClinVar).

How common is MLH1 p.Asp74= (c.222T>C) in the general population?

MLH1 p.Asp74= (c.222T>C) is very rare (popmax 0.00318%, nfe) (gnomAD).

MLH1 p.Asp74=

c.222T>C · rs755073786 · VCV237333

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00318%, nfe)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.035	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.35	phastCons 0.18
Overall
CADD	6.157	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00318% European (non-Finnish) · 37/1,163,262 alleles

Filtering AF 0.00235% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00205%

Overall 0.00232% 37/1,595,534 alleles · very rare exomes 36/1,443,388 · genomes 1/152,146 · 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: MLH1
Protein: p.Asp74=
Coding: c.222T>C
MANE Select: NM_000249
dbSNP: rs755073786
Type: single nucleotide variant
Location: chr3:37000969 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 74: a turn

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 2 hereditary neoplastic syndrome

Similar variants

MLH1 p.Asp74Asn Uncertain significance ★★ ⚠ same residue
MLH1 p.Asp74Ala Uncertain significance ★ ⚠ same residue
MLH1 p.Asp74Tyr Uncertain significance ★ ⚠ same residue
MLH1 p.Asp74Val Conflicting classifications of pathogenicity ★ ⚠ 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-asp74 (accessed [today's date]).

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