Is MSH2 p.Ser554Cys (c.1660A>T) pathogenic?

MSH2 p.Ser554Cys (c.1660A>T) is classified Pathogenic in MSH2 (ClinVar, Expert panel, 1 submitter; last evaluated 2013-09-05). AlphaMissense: likely benign (0.1225); Absent from gnomAD v4.1; Associated with Lynch syndrome.

What condition is associated with MSH2 p.Ser554Cys (c.1660A>T)?

MSH2 p.Ser554Cys (c.1660A>T) is associated with Lynch syndrome (ClinVar).

How common is MSH2 p.Ser554Cys (c.1660A>T) in the general population?

MSH2 p.Ser554Cys (c.1660A>T) is absent from gnomAD v4.1 (gnomAD).

How is Lynch syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MSH2 p.Ser554Cys (c.1660A>T)?

AlphaMissense predicts likely benign (score 0.1225) — an in-silico prediction, not a clinical call.

MSH2 p.Ser554Cys

c.1660A>T · rs63751656 · VCV90718

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1225 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Lynch syndrome

Computational evidence

Protein change
AlphaMissense	0.1225	likely benign ⚠ discordant with ClinVar
REVEL	0.783	moderately pathogenic-leaning
SaProt	LLR -10.95	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	Δ0.88	donor loss · deltas
Pangolin	Δ0.71	loss · gain 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MSH2
Protein: p.Ser554Cys
Coding: c.1660A>T
MANE Select: NM_000251
dbSNP: rs63751656
Type: single nucleotide variant
Location: chr2:47466807 (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

Lynch syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MSH2 p.Ser554Gly Pathogenic ★★★ ⚠ same residue
MSH2 p.Ser554Thr Pathogenic ★★★ ⚠ same residue
MSH2 p.Ser554= Benign/Likely benign ★★ 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 c.1076+1G>A Pathogenic ★★★ same condition
MSH2 c.1076+1G>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/msh2-p-ser554cys (accessed [today's date]).

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