Is MOS p.Trp321Ter (c.963G>A) pathogenic?

MOS p.Trp321Ter (c.963G>A) is classified Uncertain significance in MOS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-04). Very rare (popmax 0.00154%, nfe); Associated with oocyte/zygote/embryo maturation arrest 20.

What condition is associated with MOS p.Trp321Ter (c.963G>A)?

MOS p.Trp321Ter (c.963G>A) is associated with oocyte/zygote/embryo maturation arrest 20 (ClinVar).

How common is MOS p.Trp321Ter (c.963G>A) in the general population?

MOS p.Trp321Ter (c.963G>A) is very rare (popmax 0.00154%, nfe) (gnomAD).

MOS p.Trp321Ter

c.963G>A · VCV4079286

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00154%, nfe)

Conditions

oocyte/zygote/embryo maturation arrest 20

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (1 of 1) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00154% European (non-Finnish) · 18/1,168,382 alleles

Filtering AF 0.000963% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000794%

Overall 0.00126% 20/1,588,636 alleles · very rare exomes 19/1,436,386 · genomes 1/152,250 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00327%	30,619
European (non-Finnish)grpmax	0.00154%	64,910

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: MOS
Protein: p.Trp321Ter
Coding: c.963G>A
MANE Select: NM_005372
Type: single nucleotide variant
Location: chr8:56113020 (GRCh38)
Gene constraint: LOEUF 1.944 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 80.98
Residue 321: the protein kinase domain; a UniProt-annotated variant site (in ozema20; likely pathogenic; loss of function in oocyte maturation activation; loss of activation of the erk1/erk2 cascade; severely decreased interaction with map2k1)

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

Disease context

oocyte/zygote/embryo maturation arrest 20 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MOS p.Ser182Ter Likely pathogenic ★ same condition
MOS p.Ala292Val Uncertain significance ★ same condition
MOS p.His199Leu Uncertain significance ★ ⚠ same condition
MOS p.Arg246His Pathogenic ⚠ same condition
MOS p.Arg319His Pathogenic ⚠ same condition
MOS p.Asn95Lys Pathogenic ⚠ same condition
MOS p.Cys320Ter Pathogenic same condition
MOS p.Ile197Met 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/mos-p-trp321ter (accessed [today's date]).

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