Is MSH3 p.Asp48= (c.144C>T) pathogenic?

MSH3 p.Asp48= (c.144C>T) is classified Conflicting classifications of pathogenicity in MSH3 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-02). Ultra-rare (popmax 0.0212%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Asp48= (c.144C>T)?

MSH3 p.Asp48= (c.144C>T) is associated with hereditary neoplastic syndrome, familial adenomatous polyposis 4 (ClinVar).

How common is MSH3 p.Asp48= (c.144C>T) in the general population?

MSH3 p.Asp48= (c.144C>T) is ultra-rare (popmax 0.0212%, eas) (gnomAD).

MSH3 p.Asp48=

c.144C>T · rs747024539 · VCV760669

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0212%, eas)

Conditions

hereditary neoplastic syndrome

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 -0.3	GERP -3.2
Overall
CADD	4.764	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0212% East Asian · 9/42,412 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00819%

Overall 0.00152% 24/1,577,356 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0212%	4,712
Remaining individualsnot grpmax-eligible	0.00328%	30,510
European (non-Finnish)	0.00113%	88,845

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: MSH3
Protein: p.Asp48=
Coding: c.144C>T
MANE Select: NM_002439
dbSNP: rs747024539
Type: single nucleotide variant
Location: chr5:80654871 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.48 · 25 PDB
Residue 48: the 'disordered' region

Full MSH3 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

Also linked: familial adenomatous polyposis 4

Similar variants

MSH3 c.1341-2A>C Likely pathogenic ★★ same condition
MSH3 c.1341-2A>G Likely pathogenic ★★ same condition
MSH3 c.1568+1G>A Likely pathogenic ★★ same condition
MSH3 c.1568+1G>C Likely pathogenic ★★ same condition
MSH3 c.1653+1G>A Likely pathogenic ★★ same condition
MSH3 c.1653+2T>A Likely pathogenic ★★ same condition
MSH3 c.1764-1G>A Pathogenic/Likely pathogenic ★★ same condition
MSH3 c.1764-2A>C Pathogenic/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/msh3-p-asp48 (accessed [today's date]).

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