Is MSH2 p.Ser554Arg (c.1660A>C) pathogenic?

MSH2 p.Ser554Arg (c.1660A>C) is classified Conflicting classifications of pathogenicity in MSH2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-08-03). AlphaMissense: ambiguous (0.442); Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH2 p.Ser554Arg (c.1660A>C)?

MSH2 p.Ser554Arg (c.1660A>C) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 1, hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Ser554Arg (c.1660A>C) in the general population?

MSH2 p.Ser554Arg (c.1660A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MSH2 p.Ser554Arg (c.1660A>C)?

AlphaMissense predicts ambiguous (score 0.442) — an in-silico prediction, not a clinical call.

MSH2 p.Ser554Arg

c.1660A>C · rs63751656 · VCV1403555

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.442 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.442	ambiguous
REVEL	0.747	pathogenic-leaning
SaProt	LLR -8.06	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.78	donor loss · deltas
Pangolin	Δ0.62	loss · gain 0.01 · 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	26.3	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.Ser554Arg
Coding: c.1660A>C
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

Hereditary nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome 1 hereditary neoplastic syndrome

Similar variants

MSH2 p.Ser554Gly Pathogenic ★★★ ⚠ same residue
MSH2 p.Ser554Thr Pathogenic ★★★ ⚠ same residue
MSH2 p.Ser554Asn Pathogenic/Likely pathogenic ★★ ⚠ same residue
MSH2 p.Ser554= Benign/Likely benign ★★ same residue
MSH2 p.Ser554Ile Likely pathogenic ★ ⚠ same residue
MSH2 p.Ser554fs Pathogenic ★ same residue
MSH2 p.Ser554Cys 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-ser554arg (accessed [today's date]).

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