Is MSH4 p.Asp727fs (c.2179del) pathogenic?

MSH4 p.Asp727fs (c.2179del) is classified Pathogenic in MSH4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-07-01). Very rare (popmax 0.00235%, eas); Associated with spermatogenic failure 2.

What condition is associated with MSH4 p.Asp727fs (c.2179del)?

MSH4 p.Asp727fs (c.2179del) is associated with spermatogenic failure 2 (ClinVar).

How common is MSH4 p.Asp727fs (c.2179del) in the general population?

MSH4 p.Asp727fs (c.2179del) is very rare (popmax 0.00235%, eas) (gnomAD).

MSH4 p.Asp727fs

c.2179del · rs2100581757 · VCV1693504

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00235%, eas)

Conditions

spermatogenic failure 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 16 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.18	GERP -1.1, phastCons 0.99

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00235% East Asian · 1/42,468 alleles

Overall 6.5e-05% 1/1,537,316 alleles · very rare exomes 1/1,385,048 · genomes 0/152,268 · 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: MSH4
Protein: p.Asp727fs
Coding: c.2179del
MANE Select: NM_002440
dbSNP: rs2100581757
Type: Deletion
Location: chr1:75889322 (GRCh38)
Gene constraint: LOEUF 1.19 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.12
Residue 727: a UniProt-annotated variant site (in spgf2); a UniProt-annotated variant site (in spgf2; severely decreased msh4 transcript and protein levels in testicular tissue from a homozygous patient)

Full MSH4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spermatogenic failure 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MSH4 p.Arg78fs Likely pathogenic ★ same condition
MSH4 p.Pro880fs Likely pathogenic ★ same condition
MSH4 p.Lys741fs Pathogenic same condition
MSH4 p.Val269fs Pathogenic same condition
MSH4 p.Ser754Leu Pathogenic/Likely pathogenic ★★ same condition
MSH4 p.Ser733Ter Likely pathogenic ★ same condition
MSH4 c.1540+8C>A Benign ★ same condition
MSH4 c.1782-11_1782-10insAT Benign ★ 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/msh4-p-asp727fs (accessed [today's date]).

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