Is MSH2 p.Ser185Phe (c.554C>T) pathogenic?

MSH2 p.Ser185Phe (c.554C>T) is classified Uncertain significance in MSH2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-09). AlphaMissense: likely pathogenic (0.7443); Very rare (popmax 0.00333%, amr); Associated with Lynch syndrome 1.

What condition is associated with MSH2 p.Ser185Phe (c.554C>T)?

MSH2 p.Ser185Phe (c.554C>T) is associated with Lynch syndrome 1, Muir-Torre syndrome, hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Ser185Phe (c.554C>T) in the general population?

MSH2 p.Ser185Phe (c.554C>T) is very rare (popmax 0.00333%, amr) (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.Ser185Phe (c.554C>T)?

AlphaMissense predicts likely pathogenic (score 0.7443) — an in-silico prediction, not a clinical call.

MSH2 p.Ser185Phe

c.554C>T · rs878853819 · VCV237399

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.7443 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Lynch syndrome 1

Computational evidence

Protein change
AlphaMissense	0.7443	likely pathogenic
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -13.28	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,988 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000186% 3/1,613,950 alleles · very rare exomes 1/1,461,878 · genomes 2/152,072 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,994
European (non-Finnish)	8.47e-05%	1,180,025

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.Ser185Phe
Coding: c.554C>T
MANE Select: NM_000251
dbSNP: rs878853819
Type: single nucleotide variant
Location: chr2:47410281 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 185: an α-helix

Full MSH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Lynch syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Muir-Torre syndrome hereditary neoplastic syndrome mismatch repair cancer syndrome 2

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MSH2 p.Ser185= Benign/Likely benign ★★ same residue
MSH2 p.Ser185Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Ser185Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Ser185Pro Likely benign ★ same residue
MSH2 p.Ser185fs Pathogenic ★ same residue
MSH2 c.1076+1G>A Pathogenic ★★★ same condition
MSH2 c.1076+1G>T Likely pathogenic ★★★ same condition
MSH2 c.1077-1G>C 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-ser185phe (accessed [today's date]).

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