Is MLH1 p.Ser577Ter (c.1730C>A) pathogenic?

MLH1 p.Ser577Ter (c.1730C>A) is classified Pathogenic in MLH1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-07-10). No allele count reported in gnomAD v4.1 (AN 1,598,674); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MLH1 p.Ser577Ter (c.1730C>A)?

MLH1 p.Ser577Ter (c.1730C>A) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 2, hereditary neoplastic syndrome (ClinVar).

How common is MLH1 p.Ser577Ter (c.1730C>A) in the general population?

MLH1 p.Ser577Ter (c.1730C>A) is no allele count reported in gnomAD v4.1 (AN 1,598,674) (gnomAD).

MLH1 p.Ser577Ter

c.1730C>A · rs56185292 · VCV1412554

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,598,674)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 15 of 19
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.24 · evaluated, not missing
Pangolin	Δ0.21	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Overall
CADD	46.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,598,674). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MLH1
Protein: p.Ser577Ter
Coding: c.1730C>A
MANE Select: NM_000249
dbSNP: rs56185292
Type: single nucleotide variant
Location: chr3:37042330 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 577: a β-strand; the 'interaction with exo1' region

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.Ser577= Pathogenic/Likely pathogenic ★★ same residue
MLH1 p.Ser577Trp Uncertain significance ★★ ⚠ same residue
MLH1 p.Ser577Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MLH1 p.Ser577Pro Uncertain significance ★ ⚠ 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-ser577ter (accessed [today's date]).

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