Is MSH2 p.Ser554= (c.1662C>T) pathogenic?

MSH2 p.Ser554= (c.1662C>T) is classified Benign/Likely benign in MSH2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-10-30). Very rare (popmax 0.000979%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH2 p.Ser554= (c.1662C>T)?

MSH2 p.Ser554= (c.1662C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Ser554= (c.1662C>T) in the general population?

MSH2 p.Ser554= (c.1662C>T) is very rare (popmax 0.000979%, nfe) (gnomAD).

MSH2 p.Ser554=

c.1662C>T · rs587778525 · VCV134843

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000979%, nfe)

Conditions

Hereditary nonpolyposis colorectal neoplasms

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 0.59	GERP -1.8, phastCons 1
Overall
CADD	10.34	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000979% European (non-Finnish) · 10/1,021,918 alleles

Filtering AF 0.000495% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000361%

Overall 0.000834% 12/1,439,016 alleles · very rare exomes 11/1,286,918 · genomes 1/152,098 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00355%	28,193
European (non-Finnish)grpmax	0.000979%	102,192

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: MSH2
Protein: p.Ser554=
Coding: c.1662C>T
MANE Select: NM_000251
dbSNP: rs587778525
Type: single nucleotide variant
Location: chr2:47470965 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 554: an α-helix; a UniProt-annotated variant site (in lynch1; uncertain significance)

Full MSH2 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 hereditary neoplastic syndrome

Similar variants

MSH2 p.Ser554Cys Pathogenic ★★★ ⚠ same residue
MSH2 p.Ser554Gly Pathogenic ★★★ ⚠ same residue
MSH2 p.Ser554Thr Pathogenic ★★★ ⚠ same residue
MSH2 p.Ser554Asn Pathogenic/Likely pathogenic ★★ ⚠ same residue
MSH2 p.Ser554Ile Likely pathogenic ★ ⚠ same residue
MSH2 p.Ser554Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Ser554fs Pathogenic ★ same residue
MSH2 c.1076+1G>A 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/msh2-p-ser554 (accessed [today's date]).

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