Is MOS p.Pro329Arg (c.986C>G) pathogenic?

MOS p.Pro329Arg (c.986C>G) is classified Uncertain significance in MOS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely pathogenic (0.5836); Very rare (popmax 0.000516%, nfe).

How common is MOS p.Pro329Arg (c.986C>G) in the general population?

MOS p.Pro329Arg (c.986C>G) is very rare (popmax 0.000516%, nfe) (gnomAD).

What do computational predictors say about MOS p.Pro329Arg (c.986C>G)?

AlphaMissense predicts likely pathogenic (score 0.5836) — an in-silico prediction, not a clinical call.

MOS p.Pro329Arg

c.986C>G · VCV4552652

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5836 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000516%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.5836	likely pathogenic
REVEL	0.631	indeterminate
SaProt	LLR -14.40	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 1,037 bp · p 0.058 · regional, not allelic
Overall
CADD	25.6	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 0.000516% European (non-Finnish) · 6/1,163,224 alleles

Filtering AF 0.000186% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000122%

Overall 0.000444% 7/1,577,384 alleles · very rare exomes 7/1,425,048 · genomes 0/152,336 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00165%	60,748
European (non-Finnish)grpmax	0.000516%	193,871

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.Pro329Arg
Coding: c.986C>G
MANE Select: NM_005372
Type: single nucleotide variant
Location: chr8:56112997 (GRCh38)
Gene constraint: LOEUF 1.944 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 80.98
Residue 329: 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

Similar variants

MOS p.Ser182Ter Likely pathogenic ★ same type
MOS p.Ala154Thr Uncertain significance ★ ⚠ same type
MOS p.Ala247Val Uncertain significance ★ ⚠ same type
MOS p.Ala277Glu Uncertain significance ★ ⚠ same type
MOS p.Ala289Thr Uncertain significance ★ ⚠ same type
MOS p.Ala292Val Uncertain significance ★ same type
MOS p.Ala43Thr Uncertain significance ★ ⚠ same type
MOS p.Arg12Leu Uncertain significance ★ ⚠ same type

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-pro329arg (accessed [today's date]).

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