Is MSH2 p.Ser448Phe (c.1343C>T) pathogenic?

MSH2 p.Ser448Phe (c.1343C>T) is classified Uncertain significance in MSH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-19). AlphaMissense: likely benign (0.166); Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH2 p.Ser448Phe (c.1343C>T)?

MSH2 p.Ser448Phe (c.1343C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Ser448Phe (c.1343C>T) in the general population?

MSH2 p.Ser448Phe (c.1343C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about MSH2 p.Ser448Phe (c.1343C>T)?

AlphaMissense predicts likely benign (score 0.166) — an in-silico prediction, not a clinical call.

MSH2 p.Ser448Phe

c.1343C>T · VCV3874900

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.166 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.166	likely benign
REVEL	0.768	pathogenic-leaning
SaProt	LLR -9.28	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.4	GERP 1.7, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	25.1	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,530 alleles

Overall 6.2e-05% 1/1,613,254 alleles · very rare exomes 1/1,460,966 · genomes 0/152,288 · joint denominator

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.Ser448Phe
Coding: c.1343C>T
MANE Select: NM_000251
Type: single nucleotide variant
Location: chr2:47445614 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 448: an α-helix

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

Disease context

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

Similar variants

MSH2 p.Ser448= Likely benign ★★★ same residue
MSH2 p.Ser448Cys Uncertain significance ★★ ⚠ same residue
MSH2 p.Ser448Pro Uncertain significance ★ ⚠ same residue
MSH2 p.Ser448fs 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
MSH2 c.1077-1G>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-ser448phe (accessed [today's date]).

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